,PMCID,sentence_id,CONSORT_Item,labels,section,text
0,PMC3002766,S45,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"this double-blind, randomised, parallel-group, placebo-controlled study consisted of a ≤2-week screening period, a 24-week treatment period and an 8-week post-treatment follow-up period."
1,PMC3002766,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the study was approved by local ethics committees and conducted in accordance with the amended declaration of helsinki.
2,PMC3002766,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,all patients gave written informed consent.
3,PMC3002766,S49,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Settings and participants,the study was conducted from october 2003 to may 2005 at 41 centres in europe and north america.
4,PMC3002766,S50,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Settings and participants,"recruited patients were ≥18 years old, with ssc as defined by the preliminary classification criteria of the american college of rheumatology (acr)17 and at least one active du (onset between 1 week and 3 months prior to randomisation) that was selected by the investigator and termed the ‘cardinal ulcer’ (painful area, ≥2 mm in diameter with visible depth and loss of dermis, amenable to healing and in a location judged compatible with a vascular aetiology, specified by protocol as volar surface of the digit distal to the proximal interphalangeal digital crease)."
5,PMC3002766,S51,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Settings and participants,"patients were excluded if they had received intravenous prostanoids within the previous 3 months, had used phosphodiesterase inhibitors other than for intermittent treatment of male erectile dysfunction, or had received inhaled or oral prostanoids or injected botulinum toxin in an affected finger within 1 month."
6,PMC3002766,S52,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Settings and participants,patients were also excluded if they received systemic antibiotics to treat infected dus within 2 weeks prior to randomisation.
7,PMC3002766,S53,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Settings and participants,"also excluded were patients with body weight <40 kg, severe pah (who class iii/iv), moderate to severe hepatic impairment or serum aminotransferase levels >3 times the upper limit of the normal range (uln)."
8,PMC3002766,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Settings and participants,contraceptive measures and monthly pregnancy testing were required during and for 3 months after the end of study treatment.
9,PMC3002766,S56,"['8a', '8b']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Randomisation and interventions,"after screening, patients were randomised to bosentan or placebo (1:1 ratio) by sequential allocation of randomisation numbers distributed to each centre in blocks of four."
10,PMC3002766,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomisation and interventions,patients received bosentan 62.5 mg twice daily for 4 weeks and then 125 mg twice daily for the remainder of the treatment period or matching placebo.
11,PMC3002766,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomisation and interventions,"the dose could remain at or be decreased to the starting dose due to intolerance, with possible subsequent increase to the target dose."
12,PMC3002766,S59,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomisation and interventions,"concomitant use of systemic antibiotics, analgaesics and topical treatments for wound care were allowed, and randomised treatment was administered in addition to the usual, stable (over the previous month) treatment for raynaud's phenomenon."
13,PMC3002766,S60,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomisation and interventions,"patients who required parenteral, oral or inhaled prostanoid treatment during the study were first discontinued from study treatment."
14,PMC3002766,S61,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomisation and interventions,"use of glibenclamide, fluconazole, calcineurin inhibitors or ciclosporin a was not allowed due to potential drug interactions."
15,PMC3002766,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the two primary end points were (1) the mean number of new dus per patient assessed by the investigator up to week 24 and (2) the time to healing of the cardinal ulcer up to week 24 in patients with cardinal ulcer healing maintained for 12 or more weeks.
16,PMC3002766,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"healing was defined as complete epithelialisation, regardless of residual pain."
17,PMC3002766,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,maintenance of cardinal ulcer healing required no recurrence at or contiguous to the original location at week 24 (if healing occurred before or at week 12) or during 12 weeks of observation with permissible extension of the treatment period (if healing occurred after week 12).
18,PMC3002766,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"to verify that the effect of treatment would not vary substantially across relevant baseline subgroups, the number of new dus up to week 24 was additionally analysed in subgroups based on predefined baseline factors associated with disease severity."
19,PMC3002766,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"secondary and exploratory end points included: (1) reduction of new dus and overall du number (proportions of patients with no new dus and with each number of new dus up to week 24, time to onset of each number of new dus up to week 24 and change from baseline to week 24 in total number of all dus), (2) healing (time to healing of all baseline dus and of all new dus through week 24, and proportions of patients with healing of all dus by the end of week 24) and (3) pain and disability parameters (changes from baseline to week 24: in pain of the cardinal ulcer and overall hand pain assessed on visual analogue scales; hand disability index (an averaged score from the three health assessment questionnaire (haq) domains of dressing/grooming, grip and hygiene); and haq disability index18 19)."
20,PMC3002766,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"post hoc analyses included: (1) the number of new dus up to week 12 in the overall patient population and in subgroups defined by randomisation month (october–february or autumn–winter and march–september or spring–summer) and (2) number of new dus, time to each successive new du and total number of dus through week 24 in subgroups defined by the number of dus at baseline (<4 and ≥4)."
21,PMC3002766,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,"patients were evaluated at randomisation/baseline and every 4 weeks during treatment (or premature withdrawal, week 24 and, if applicable, 12 weeks after healing of the cardinal ulcer), with dus assessed at each study visit."
22,PMC3002766,S70,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,safety was continually monitored.
23,PMC3002766,S72,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"efficacy analyses were performed on all treated patients using sas software (sas institute, cary, north carolina, usa)."
24,PMC3002766,S73,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,means±ses are presented for numerical variables and kaplan–meier estimates for time-to-event variables.
25,PMC3002766,S74,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,treatment effects for the primary end points were evaluated using the pitman permutation (new dus) and log-rank test with asymptotic approximation (time to healing of the cardinal ulcer).
26,PMC3002766,S75,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"missing data on new dus were imputed using extrapolation, with the incidence rate of new dus at the last assessment corrected for the missing time period."
27,PMC3002766,S76,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,the worst of either the calculated number or observed values at week 24 was used for patients who prematurely discontinued study treatment.
28,PMC3002766,S77,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"patients with no valid assessment post baseline (three patients on bosentan, one on placebo) were excluded from the main analysis."
29,PMC3002766,S78,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,treatment effects for new dus in predefined subgroups were presented as point estimates and 95% two-sided cis.
30,PMC3002766,S79,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"for exploratory purposes, statistical tests of treatment difference were provided for planned secondary/exploratory and unplanned post hoc efficacy analyses and included the pitman permutation (for changes from baseline), the fisher exact test (for proportions) and the log-rank test (for times to event), each performed without correction for multiple testing."
31,PMC3002766,S80,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"placebo-corrected changes from baseline, rr and hrs from cox modelling were each reported with 95% cis where appropriate."
32,PMC3002766,S81,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"safety and baseline data were summarised descriptively, with no statistical testing planned or given."
33,PMC3002834,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study subjects,"we studied a subgroup of crs patients from the epocares trial (clinicaltrials.gov, nct00356733), and healthy controls of comparable age and gender."
34,PMC3002834,S50,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study subjects,a detailed description with inclusion and exclusion criteria of the study has previously been published.14
35,PMC3002834,S51,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study subjects,the protocol was approved by the medical ethics committee and all patients gave informed consent.
36,PMC3002834,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study subjects,procedures were in accordance with the helsinki declaration.
37,PMC3002834,S53,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study subjects,"patients with mild anaemia (women: 6.4–7.4 mmol/l; men: 6.4–7.8 mmol/l), moderate ckd (estimated creatinine clearance 20–70 ml/min, cockcroft–gault formula) and chf (functional nyha class ii–iv, based on symptoms, signs and objective abnormality on echocardiography,15 reduced ejection fraction (<50%) or left ventricular end-diastolic volume index <97 ml/m2 with evidence of diastolic left ventricular dysfunction16) were included."
38,PMC3002834,S55,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,epc levels and function were compared between 45 crs patients at baseline and 20 healthy controls.
39,PMC3002834,S56,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"the effects of epo treatment were evaluated in an open-label, randomised design."
40,PMC3002834,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"patients received epo treatment (50 iu/kg/week; neorecormon, roche pharmaceuticals, woerden, netherlands) or standard treatment without epo for one year."
41,PMC3002834,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,"short-term effects of epo (n =30) versus no epo (n =15) were evaluated after 18 days (3 days after third epo injection), when epo treatment was not yet expected to result in a haematopoietic response."
42,PMC3002834,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,"long-term (52 week) effects of epo were assessed in a subgroup of epo-treated patients, who were allowed to increase haemoglobin (hb) levels up to 8.5 mmol/l for men and 8.3 mmol/l for women (n =13), and a non epo-treated group (n =13)."
43,PMC3002834,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Plasma measurements,"serum epo levels were measured by sandwich chemiluminescent immunoassay (immulite 2000 platform, siemens healthcare diagnostics, breda, netherlands)."
44,PMC3002834,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Plasma measurements,"endothelial dysfunction, epc mobilising factors and inflammation markers were measured using elisa (e-selectin, vascular cell adhesion molecule-1 (vcam-1), interleukin (il)-6, vegf, sdf-1α (r&d systems, minneapolis, minnesota, usa) and thrombomodulin (diaclone, stamford, connecticut, usa)) or multiplex immunoassay17 (intercellular adhesion molecule-1 (icam-1) and monocyte chemotactic protein-1 (mcp-1) (bio-rad laboratories,hercules, california, usa))."
45,PMC3002834,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Plasma measurements,"high sensitivity c reactive protein (hscrp) was determined by particle-enhanced immunonephelometry (standard cardio-phase hscrp for bnii, dade behring holding, liederbach, germany)."
46,PMC3002834,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Plasma measurements,"n-terminal prohormone of brain natriuretic peptide (nt-probnp) was measured using electrochemiluminescense immunoassay (cobas ca6000, roche, mannheim, germany)."
47,PMC3002834,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Plasma measurements,samples were measured in duplicate and averaged for analysis.
48,PMC3002834,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Circulating EPC levels,"circulating epc were defined as cells positive for haematopoietic stem cell marker cd34 and endothelial marker kinase insert domain receptor (kdr; ie, vegf receptor-2)."
49,PMC3002834,S68,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Circulating EPC levels,this cd34+kdr+-epc has previously shown clinical importance by predicting cardiovascular events and death in cardiovascular risk populations.18 19
50,PMC3002834,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Circulating EPC levels,"blood (100 μl) was incubated with anti-cd34-fitc (bd pharmingen, california, usa), anti-kdr-pe (r&d systems) and anti-cd45-pe-cy7 (bd pharmingen) antibodies for 45 min. erythrocytes were lysed and analysed by flow cytometry (beckman coulter, california, usa)."
51,PMC3002834,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Circulating EPC levels,circulating hsc and epc were identified as cd34+ and cd34+kdr+ cells in the lymphocyte region of the forward/sideward scatter plot.
52,PMC3002834,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Circulating EPC levels,"cell numbers were quantified relative to 105 granulocytes, identified as cd45+ cells with a typical granulocyte distribution."
53,PMC3002834,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Circulating EPC levels,measurements were performed in duplicate and results were averaged.
54,PMC3002834,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Circulating EPC levels,isotype-stained samples served as negative controls.
55,PMC3002834,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outgrowth of EPC in culture,epc outgrowth from mononuclear cells (mnc) was assessed as described previously.3
56,PMC3002834,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outgrowth of EPC in culture,"in brief, mnc were isolated from blood using ficoll density gradient separation (histopaque 1077, sigma, st louis, missouri, usa)."
57,PMC3002834,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outgrowth of EPC in culture,"to evaluate epc outgrowth in culture, 107 mnc/well were seeded on a human fibronectin (sigma) coated 6-well plate in egm-2 (cambrex, baltimore, maryland, usa), supplemented with accompanying aliquots, 20% fetal calf serum (invitrogen, carlsbad, california, usa), 100 ng/ml recombinant vegf-165 (r&d systems) and antibiotics."
58,PMC3002834,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outgrowth of EPC in culture,medium was changed after 4 days to wash non-adherent cells away.
59,PMC3002834,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outgrowth of EPC in culture,"after 7 days, cultured epc in selected wells were placed on serum free medium (ebm-2 with hegf, hydrocortisone, ga-1000, r3-igf-1, ascorbic acid, heparin and antibiotics) overnight."
60,PMC3002834,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outgrowth of EPC in culture,"conditioned medium was stored for functional experiments and cultured epc were detached by trypsin and cell scraping, and automatically counted using a haemocytometer."
61,PMC3002834,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",In vitro scratch wound assay,the potential of epc outgrowth to excrete paracrine factors that stimulate endothelial cell migration was assessed by in vitro scratch wound assay.20
62,PMC3002834,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",In vitro scratch wound assay,"in brief, epc outgrowth medium was placed on a mechanically scratched confluent human microvascular endothelial cell layer."
63,PMC3002834,S84,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",In vitro scratch wound assay,"after 6 h, the extent of scratch closure relative to the starting width was compared between study groups using light photography."
64,PMC3002834,S85,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",In vitro scratch wound assay,each sample was measured in two separate wells and two picture fields per well were examined.
65,PMC3002834,S86,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",In vitro scratch wound assay,results were averaged for data analysis.
66,PMC3002834,S88,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,data analysis was performed using spss v.15.0 for windows.
67,PMC3002834,S89,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,data distribution was tested by the kolmogorov–smirnov test.
68,PMC3002834,S90,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,data are expressed as mean ± sd for parametric data and as median (iqr) for non-parametric data.
69,PMC3002834,S91,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,differences between groups were analysed using student's t test or the mann–whitney test.
70,PMC3002834,S92,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,fisher's exact test was used to analyse whether proportions of categories varied by group.
71,PMC3002834,S93,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,multiple group comparisons were performed using anova with lsd post-hoc testing for which non-parametric data were log-transformed.
72,PMC3002834,S94,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,correlations were measured by pearson's or spearman's correlation coefficient where appropriate.
73,PMC3002834,S95,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,multivariate determinants of log-transformed progenitor cell counts were identified by stepwise multiple linear regression analysis.
74,PMC3002834,S96,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,a value of p <0.05 was considered statistically significant.
75,PMC3016167,S100,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study treatments,"mesobuthus tamulus is not the only venomous scorpion in the state of western maharashtra, but it may be the only dangerously venomous scorpion in the mahad area.24 25"
76,PMC3016167,S101,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study treatments,haffkine biopharma (mumbai) has been manufacturing monovalent anti-scorpion venom serum f(ab)2 against mesobuthus tamulus since 1997 and it has been available for clinical use in a rural setting since 2002.
77,PMC3016167,S102,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study treatments,studies conducted at different times show that the antivenom is potent; 1 ml of reconstituted anti-scorpion venom serum neutralised 1.2 mg of indian red scorpion venom by intravenous route in an in vivo study in mice.35
78,PMC3016167,S103,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study treatments,"the maximum volume of venom injected in one sting by the indian red scorpion is 1.5 mg, and each ml of antivenom is capable of neutralising 1.2 to 1.5 mg of venom.36"
79,PMC3016167,S104,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatments,"a single 30 ml dose of haffkine biopharma monovalent antivenom (batch no ss811001, manufacturing date november 2008, expiry date april 2013) was added to 100 ml of normal saline, which was infused intravenously over 30 minutes irrespective of patient’s age."
80,PMC3016167,S105,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatments,"during infusion the patient was closely observed for reaction to the serum in the form of sudden onset of vomiting, urticaria, hypotension, tachycardia, bronchospasm, angioneurotic oedema, or anaphylaxis."
81,PMC3016167,S106,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatments,"oral prazosin (batch no ml.nh 138 batch no gk 60372 manufactured 04/2006, expiry 03/2011, and ml.nh 138 batch no gk 80282 manufactured 02/2008, expiry 01/2013) was given at a dose of 250 µg in children up age 18 years and 500 µg in adults."
82,PMC3016167,S107,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatments,the same dose was repeated at intervals of 3 hours until the extremities were cold.
83,PMC3016167,S108,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatments,similar doses were administered in both randomisation groups.
84,PMC3016167,S109,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatments,dehydration owing to vomiting and sweating was corrected by intravenous crystalloid solution.
85,PMC3016167,S110,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatments,the prazosin treated group required longer duration and larger volumes of intravenous crystalloid solution than the antivenom plus prazosin group.
86,PMC3016167,S111,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatments,patients who developed grade 3 and 4 symptoms were transferred to the intensive care unit.
87,PMC3016167,S112,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatments,before discharge all participants were immunised for tetanus.
88,PMC3016167,S114,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the primary end point was the proportion of patients achieving resolution of the grade 2 clinical syndrome at the end of 10 hours after administration of the study drugs and prevention of deterioration to grade 3 and 4.18 21 37
89,PMC3016167,S115,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"secondary end points were time required for complete resolution of clinical syndrome, prevention of deterioration to higher grade, doses of prazosin required within 10 hours and overall, and adverse events."
90,PMC3016167,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,this study and trial were done without the help of any funding agency.
91,PMC3016167,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,anti-scorpion antivenom was purchased from haffkine biopharma mumbai and given to participants in this trial.
92,PMC3016167,S48,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,"we proposed to include people admitted with scorpion sting over one year, between march 2009 and february 2010."
93,PMC3016167,S49,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,"this was a randomised (1:1 allocation ratio), parallel group, open label, controlled trial conducted at bawaskar hospital in mahad, a region of india with a population of 20 000, situated 180 km south of mumbai on the mumbai-goa highway."
94,PMC3016167,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,an independent data and safety monitoring board monitored the trial and had access to the all data.
95,PMC3016167,S51,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,statistical analysis was done by a statistician in collaboration with the investigators.
96,PMC3016167,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,the study design was approved by the independent ethics committee of byl medical college mumbai (iec/08/39) and all participants provided written informed consent.
97,PMC3016167,S54,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Sample size,the primary efficacy variable was the time required for recovery after venomous scorpion sting.
98,PMC3016167,S55,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"we estimated that 35 patients in each group would be required to achieve 80% power; α=0.05 to detect a mean difference of four hours in the recovery time between the groups, assuming a mean recovery time of 10 hours (sd 2.5 hours) in the antivenom plus prazosin group and 14 (sd 3) hours for the prazosin alone group."
99,PMC3016167,S57,"['8a', '8b']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Randomisation,a statistician generated the sequentially numbered randomisation list with random block sizes of 4 4 2 4 4 6 2 4 6 6 6 8 4 8 2 using www.randomisation.com.
100,PMC3016167,S58,['8a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Randomisation,this process can be reproduced by using seed 22491 (6 march 2009).
101,PMC3016167,S59,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Randomisation,"this randomisation sequence was concealed by using sequentially numbered, opaque, sealed, and stapled envelopes."
102,PMC3016167,S60,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,envelopes were opened alternately by hsb or phb after an eligible patient consented to take part in the trial and patients were allocated according to the randomisation label inside the envelope.
103,PMC3016167,S62,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,demographic factors and clinical characteristics were summarised as counts (percentages) for categorical variables and as mean (standard deviation; sd) for normally distributed continuous variables.
104,PMC3016167,S63,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,all patients who had been randomly assigned to a treatment group were included in the intention-to-treat analyses.
105,PMC3016167,S64,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"the groups were compared using χ2 test or fisher’s exact test for categorical variables, unpaired t test for normally distributed continuous variables, and mann-whitney u test for other continuous variables."
106,PMC3016167,S65,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,we analysed results with spss 17 software.
107,PMC3016167,S66,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"blood pressure and pulse rate were measured at different time points and were repeated factors, and treatment group was included as a between-participant measure."
108,PMC3016167,S67,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,α was set at 0.05.
109,PMC3016167,S68,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,we used the greenhouse-geisser p value.
110,PMC3016167,S70,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,between march 2009 and february 2010 we recruited patients who reported to bawaskar hospital and mahad research centre after being stung by mesobuthus tamulus (fig 1).2 4 6 31
111,PMC3016167,S71,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,fig 1 indian red scorpion (mesobuthus tamulus)
112,PMC3016167,S73,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Inclusion and exclusion criteria,"patients were eligible for enrolment if they reported to hospital with mesobuthus tamulus sting of clinical grade 2 severity, with an interval of less than six hours between sting and hospital admission, and were older than six months."
113,PMC3016167,S74,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Inclusion and exclusion criteria,"mesobuthus tamulus sting was confirmed if the victim or bystander had seen a red scorpion, had brought in the killed specimen, or recognised the hospital’s preserved specimen."
114,PMC3016167,S75,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Inclusion and exclusion criteria,"in this way we made sure that mesobuthus tamulus was not confused with palamneus gravimanus, a larger scorpion that is less lethal and causes only severe local pain without systemic involvement or transient reversible cardiovascular effects.1 32"
115,PMC3016167,S76,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Inclusion and exclusion criteria,"major exclusion criteria were: patient reporting six hours after sting, pregnant women, history of taking prazosin or antivenom, history of bronchial asthma, history of allergic reaction to foreign serum, and refusal to give consent."
116,PMC3016167,S77,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Inclusion and exclusion criteria,written informed consent was obtained in the local language.
117,PMC3016167,S78,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Inclusion and exclusion criteria,"for illiterate adults, a literate relative of the patient read the statement out loud to them and consent was obtained by thumb impression witnessed by the relative."
118,PMC3016167,S79,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Inclusion and exclusion criteria,parent’s consent was obtained for minor children.
119,PMC3016167,S80,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Inclusion and exclusion criteria,"the study protocol was approved by the independent ethics committee of mumbai (registration number 1433/1999g.b.b.s.d, iec/08/39)."
120,PMC3016167,S81,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Inclusion and exclusion criteria,all people admitted with scorpion sting between march 2009 to february 2010 were insured by the oriental insurance company limited clinical trial liability cover policy no 111600/48/2009/227.
121,PMC3016167,S83,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,cases are graded according to severity of clinical manifestations on arrival at hospital (box).
122,PMC3016167,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"severity of clinical manifestations, morbidity, and mortality depend on the time lapsed between sting and hospital admission, as well as the grade of a case on arrival.5 9 18 33 34"
123,PMC3016167,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"grade 1: severe, excruciating local pain at the sting site radiating along with corresponding dermatomes, mild local oedema with sweating at the sting site, without systemic involvement"
124,PMC3016167,S87,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"grade 2: signs and symptoms of autonomic storm characterised by acetylcholine excess or parasympathetic stimulation (vomiting, profuse sweating from all over body, ropey salivation, bradycardia, premature ventricular contraction, hypotension, priapism in men) and sympathetic stimulation (hypertension with blood pressure >140/90, tachycardia with heart rate >120 per minute, cold extremities, transient systolic murmur)."
125,PMC3016167,S88,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"grade 3: cold extremities, tachycardia, hypotension or hypertension with pulmonary oedema (respiratory rate >24 per minute, basal rales or crackles in lungs)."
126,PMC3016167,S89,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"grade 4: tachycardia, hypotension with or without pulmonary oedema with warm extremities (warm shock)."
127,PMC3016167,S90,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,patients with grade 2 signs and symptoms were included in the present study.
128,PMC3016167,S91,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"after giving written consent, all eligible patients were examined by one of the two authors and baseline data were recorded on a standard form."
129,PMC3016167,S92,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"data included age, sex, time between sting and hospital admission, and history of any medication before admission, vomiting soon after sting, or paraesthesia (tingling and numbness in the perioral region, or sometimes reported by the patient to be felt all over the body)."
130,PMC3016167,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"one of the authors sat by the side of the patients and closely clinically examined them for signs and symptoms of systemic manifestations: presence of profuse sweating all over the body, ropey salivation, priapism in men, heart murmur, coolness of the extremities."
131,PMC3016167,S94,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"blood pressure, heart rate, cardiac arrhythmias, respiratory rate, and oxygen saturation were monitored on a multipara monitor."
132,PMC3016167,S95,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"these findings were noted on admission at 00.00, at 30 minutes, and at 1, 2, 4, 6, 8, 10, 14, 18, and 24 hours."
133,PMC3016167,S96,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,subsequent improvement or deteriorations to grade 3 or 4 were closely followed by the author who examined the patient on arrival.
134,PMC3016167,S97,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"blood was collected from all participants on admission for measurement of haemoglobin, white cell count, and creatine kinase-mb."
135,PMC3016167,S98,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Evaluation of clinical grade,"a 12 lead electrocardiogram (ecg) was done on arrival, after six hours, and before discharge."
136,PMC3018567,S100,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"on the basis of our preliminary study,32 the planned cohort size of 2500 was expected to accrue 1860 person-years of follow-up in infancy and 1594 infants were expected to be seen at age 1 year."
137,PMC3018567,S101,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"for either maternal treatment, assuming no interaction between treatments, this number would give 80% power to detect rate ratios of 0·82 for malaria, 0·91 for diarrhoea, and 0·76 for pneumonia, with p values of less than 0·05, assuming frequency of disease in the placebo groups to be 50 per 100 person-years for malaria,33 190 per 100 person-years for diarrhoea,34 and 25 per 100 person-years for pneumonia.35"
138,PMC3018567,S102,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"incidence of both tuberculosis and measles was expected to be low,18 therefore only very large differences in incidence would be detected."
139,PMC3018567,S103,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"samples from 1594 infants assessed at 1 year would detect differences in infant cytokine responses of 0·11 log10 between intervention groups.18,32"
140,PMC3018567,S104,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the patients that were included in analysis for each of the primary outcomes differed because data for each outcome was obtained at different times.
141,PMC3018567,S105,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for immune response at age 1 year, analysis included all children who provided a blood sample at 1 year and who had received full bcg (for ccfp analysis) or tetanus (for tetanus toxoid analysis) immunisation at entebbe hospital; second-born twins were excluded."
142,PMC3018567,S106,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for incidence of infectious diseases during infancy, analysis included all liveborn children, excluding second-born twins."
143,PMC3018567,S107,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for vertical hiv transmission, analysis included all children whose mothers were not receiving highly-active antiretroviral therapy, and from whom blood samples at age 6 weeks were available; second-born twins were excluded."
144,PMC3018567,S108,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"cytokine and antibody responses showed skewed distributions, with disproportionate numbers of zero values."
145,PMC3018567,S109,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,results were transformed to log10(concentration+1) and analysed by linear regression with bootstrapping to estimate bias-corrected accelerated confidence intervals.36
146,PMC3018567,S110,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,regression coefficients were back-transformed to give geometric mean ratios.
147,PMC3018567,S111,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,interactions were examined with wald tests.
148,PMC3018567,S112,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for doctor-diagnosed disease incidence, time at risk began at birth and was censored at loss to follow-up, death, or age 1 year."
149,PMC3018567,S113,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all children with known date of birth were included in the analysis until censoring, irrespective of whether they had made a clinic visit for illness."
150,PMC3018567,S114,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for each disease, we calculated incidence rates for all events."
151,PMC3018567,S115,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"disease episodes within 14 days of an initial presentation with the same disease were regarded as part of the same episode and excluded from the analysis; time at risk was adjusted accordingly, excluding these 14-day periods from the total person-time denominator."
152,PMC3018567,S116,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"hazard ratios (hrs) for effects of treatment were calculated with cox regression, with robust ses to allow for within-child clustering."
153,PMC3018567,S117,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for community-reported illness data, a generalised-estimating-equation approach with exchangeable correlation structure was used to model effects of treatment on repeated binary outcomes."
154,PMC3018567,S118,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,odds ratios (ors) for the effects of treatment on vertical hiv transmission were calculated with logistic regression.
155,PMC3018567,S119,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the prevalence of asymptomatic malaria at 1 year was compared between treatment groups with logistic regression.
156,PMC3018567,S120,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"infant mortality per 1000 livebirths was estimated from kaplan-meier survival probabilities to age 1 year, and effects of maternal anthelmintic treatment were assessed by cox regression."
157,PMC3018567,S121,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"weight-for-age, height-for-age, and weight-for-height z scores at 1 year were derived from who growth standard reference scales, with igrowup macros."
158,PMC3018567,S122,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we examined effects of maternal treatment on z scores and on haemoglobin at 1 year by linear regression.
159,PMC3018567,S123,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we did two prespecified subgroup analyses, examining effects of albendazole treatment in children of mothers with a hookworm infection, and effects of praziquantel treatment in children of mothers with schistosomiasis."
160,PMC3018567,S124,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,differences between subgroups were examined by fitting interaction terms in regression models.
161,PMC3018567,S125,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,all p values were two-sided with no adjustment made for multiple comparisons.
162,PMC3018567,S126,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,analyses were done with stata 10.1.
163,PMC3018567,S128,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,"the sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report."
164,PMC3018567,S129,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,ame had full access to all the data in the study and had final responsibility for the decision to submit for publication.
165,PMC3018567,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,the study is described in detail elsewhere.18
166,PMC3018567,S47,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"briefly, the study area was entebbe municipality and katabi subcounty, beside lake victoria, uganda."
167,PMC3018567,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"the area is occupied by urban, rural, and fishing communities."
168,PMC3018567,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"helminth infection is highly prevalent in the area,19 and malaria, diarrhoea, and pneumonia are common in young children.20"
169,PMC3018567,S50,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"the study population consisted of pregnant women who presented at the government-funded antenatal clinic at entebbe general hospital between april 9, 2003, and nov 24, 2005, where roughly 70% of pregnant women from the study area received antenatal care.21"
170,PMC3018567,S51,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"women were included if resident in the study area, planning to deliver in the hospital, willing to know their hiv status, and in the second or third trimester of pregnancy."
171,PMC3018567,S52,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"they were excluded if they had possible helminth-induced pathological changes (haemoglobin <80 g/l, clinically apparent severe liver disease, or diarrhoea with blood in stool), a history of an adverse reaction to anthelmintics, already been enrolled in the trial during an earlier pregnancy, or if the pregnancy was deemed abnormal by a midwife."
172,PMC3018567,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"all participants gave written, informed consent."
173,PMC3018567,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"ethics approval was given by the uganda virus research institute, uganda national council for science and technology, and london school of hygiene and tropical medicine."
174,PMC3018567,S56,"['8b', '5', '3a']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 1, 0]",Randomisation and masking,"we used a two-by-two factorial design to randomly assign patients in a 1:1:1:1 ratio to receive simultaneously either single-dose albendazole (440 mg) and single-dose praziquantel (40 mg/kg), albendazole and a praziquantel-matching placebo, an albendazole-matching placebo and praziquantel, or an albendazole-matching placebo and a praziquantel-matching placebo (albendazole and matching placebo, glaxosmithkline, brentford, uk; praziquantel and matching placebo, medochemie ltd, limassal, cyprus)."
175,PMC3018567,S57,"['8a', '8b']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Randomisation and masking,"the randomisation code was generated by the trial statistician with a computer-generated random number sequence, with block size 100."
176,PMC3018567,S58,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Randomisation and masking,treatments were packed in sealed envelopes and labelled with an allocation number by colleagues at the medical research council unit in entebbe who did not otherwise contribute to the trial.
177,PMC3018567,S59,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,treatments were allocated in numerical order by trained interviewer-counsellors who observed the patients taking the treatment correctly on enrolment to the study.
178,PMC3018567,S60,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,treatment allocation was masked from all participants and staff during the study.
179,PMC3018567,S62,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"demographic and clinical details, and blood samples were obtained at screening; stool samples were obtained before enrolment."
180,PMC3018567,S63,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"after enrolment, women continued to receive standard antenatal care, including haematinics, tetanus immunisation, and intermittent presumptive treatment for malaria twice after their first trimester of pregnancy; women with hiv were offered intrapartum and neonatal single-dose nevirapine for prevention of mother-to-child (vertical) hiv transmission.22"
181,PMC3018567,S64,"['5', '6a']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0]",Procedures,"stool samples were obtained after delivery to assess effectiveness of anthelmintic treatment; thereafter, all mothers received praziquantel and albendazole."
182,PMC3018567,S65,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"infants received bcg and polio immunisation at birth; diphtheria, pertussis, tetanus, haemophilus influenzae, hepatitis b, and polio immunisation at 6, 10, and 14 weeks; and measles immunisation at 9 months."
183,PMC3018567,S66,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"children also attended the study clinic when unwell; doctors diagnosed, treated, and recorded their illnesses."
184,PMC3018567,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"community fieldworkers visited each participant's home twice a month, measured the child's temperature, and recorded symptoms reported by the child's carer."
185,PMC3018567,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"at age 12 months, blood and stool samples were obtained from the children and growth outcomes were measured."
186,PMC3018567,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,children who were unwell at their 12-month visit were given appropriate treatment and asked to return to complete the visit procedures when well.
187,PMC3018567,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"the primary outcomes were immune response at age 1 year to bcg, tetanus, and measles immunisation; incidence of malaria, diarrhoea, pneumonia, measles, and tuberculosis during infancy as diagnosed by doctors at the study clinic; and vertical hiv transmission.18"
188,PMC3018567,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,planned secondary outcomes were growth and anaemia at age 1 year.
189,PMC3018567,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,community-reported data for illness events were included as a secondary outcome for comparison with doctor-diagnosed illness events from clinic visits.
190,PMC3018567,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,we also considered two additional unplanned secondary outcomes: infant mortality and asymptomatic malaria (presence of malaria parasitaemia) at 1 year of age.
191,PMC3018567,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,cytokine responses at 1 year of age to crude culture filtrate proteins of mycobacterium tuberculosis (ccfp) were measured as an indicator of response to bcg immunisation.
192,PMC3018567,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,cytokine responses at age 1 year to tetanus toxoid were measured as an indicator of response to tetanus immunisation.
193,PMC3018567,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"we examined stimulated interferon-γ (type 1), interleukin-5 (type 2), interleukin-13 (type 2), and interleukin-10 (regulatory) responses in a whole-blood assay, as previously described.23"
194,PMC3018567,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"total serum igg, igg4, and ige responses to tetanus toxoid were measured by elisa (webappendix p 1)."
195,PMC3018567,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"total serum measles-specific igg was measured by elisa (dade behring/siemens, eschborn, germany) according to the manufacturer's protocol."
196,PMC3018567,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"immunological assays were done after all samples had been obtained, in a randomised sequence (by use of a computer-generated random number sequence), to avoid confounding of secular trends with variations in assay performance."
197,PMC3018567,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"for the primary outcome, doctor-diagnosed illness events, clinical malaria was fever (temperature ≥37·5°c) with parasitaemia; diarrhoea was an infant's carer's definition, with stool frequency recorded;24 pneumonia was cough with difficulty in breathing, and age-specific fast breathing;25 measles was defined by standard clinical criteria and confirmed by measurement of specific antibody;26 and children with suspected tuberculosis were investigated as clinically indicated.27"
198,PMC3018567,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"for the secondary outcome, community-reported illnesses, febrile illness was defined as measured by fieldworkers (temperature ≥37·5°c) or as reported by the child's carer; diarrhoea as reported by the carer, with stool frequency recorded; presumptive pneumonia was cough with difficulty in breathing, or age-specific fast breathing as measured by fieldworkers."
199,PMC3018567,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"stool samples were examined for helminth ova with the kato-katz method28 and by charcoal culture for strongyloides sterocoralis infection;29 two kato-katz slides were prepared from each sample and examined for hookworm ova within 30 mins of preparation, or examined the next day for other species."
200,PMC3018567,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"hookworm and schistosoma mansoni infections were classified into low, medium, and high intensities according to who guidelines.30"
201,PMC3018567,S84,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,blood samples were examined by a modified knott's method for mansonella perstans31 and by thick film for malaria parasites.
202,PMC3018567,S85,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"haemoglobin was estimated by coulter analyser (beckman coulter, nyon, switzerland)."
203,PMC3018567,S86,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"quality control for kato-katz analyses was provided by the vector control programme of the ministry of health, uganda, and for haematology and malaria parasitology through the uk national external quality assessment schemes."
204,PMC3018567,S87,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,mothers' hiv serology was done by rapid test algorithm.30
205,PMC3018567,S88,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,blood was obtained from cord and at 6 weeks of age from infants of mothers with hiv for assessment of vertical hiv transmission.
206,PMC3018567,S89,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,plasma and whole blood cell pellet were separated by centrifugation and stored at −80°c until assays were done.
207,PMC3018567,S90,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"for detection of hiv-1 proviral dna in infants at 6 weeks, dna was extracted from stored whole blood cell pellets and amplified by nested pcr of three conserved viral regions, tat, gp41, and nef (webappendix p 1)."
208,PMC3018567,S91,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"for both cord and 6-week samples, plasma hiv load was measured with bayer versant branched dna assay version 3.0 (bayer, leverkusen, germany) or roche amplicor hiv-1 rna monitor test version 1.5 (roche, nj, usa)."
209,PMC3018567,S92,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"infants were regarded as being hiv positive if the 6-week sample had a positive dna pcr for any of the viral regions and a viral load of 1000 copies per ml or more; for four infants, only viral load data were available, so they were used to establish hiv status."
210,PMC3018567,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"viral load and dna-pcr results were concordant apart from one infant (viral load 6699 copies per ml, pcr negative) who was seronegative by rapid test algorithm at age 18 months and was classified as hiv negative."
211,PMC3018567,S94,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"in infants with hiv infection, transmission was regarded as likely to have been intrauterine if the viral load in cord blood was 1000 copies per ml or more."
212,PMC3018567,S96,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,analysis was done after all children were older than 15 months.
213,PMC3018567,S97,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"data for samples and measurements obtained at routine, 1-year visits were included if the child attended within 2 months after their first birthday."
214,PMC3018567,S98,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,data for illness events and mortality were censored strictly at 1 year.
215,PMC3018567,S99,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,results for younger twins were excluded from all analyses.
216,PMC3028347,S100,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"bmi z change (or change in each secondary outcome variable) was the dependent variable; metformin treatment was the independent variable; and age, sex, and race/ethnicity were covariates."
217,PMC3028347,S101,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,we then combined the coefficients from analyses of the 20 imputed datasets into a single set of estimates according to rubin’s rules for scalar estimands.
218,PMC3028347,S102,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"to assess sensitivity of the results to the missing-at-random assumption, we conducted three additional analyses: assuming that all participants who withdrew from the study had major weight gain (≥2.27 kg [≥5 lb]); that those who received metformin had no weight gain, whereas those who received placebo had major weight gain; and that those who received placebo had no weight gain, whereas those who received metformin had major weight gain."
219,PMC3028347,S103,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,we used multiple imputations to impute the missing 6-month weight measurements by using the same imputation model used for the main analysis.
220,PMC3028347,S104,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"for the three scenarios, we added fixed amounts to the imputed values, reanalyzed the results by using ancova, and combined them by using the rubin rules for scalar estimands."
221,PMC3028347,S105,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,an additional confirmatory analysis used the last-observation-carried-forward method for individuals who did not complete the study.
222,PMC3028347,S106,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,unadjusted analyses were also run both for the imputation and the last-observation-carried-forward models.
223,PMC3028347,S107,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"because all of these models yielded similar results, only the primary efficacy model is presented."
224,PMC3028347,S108,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"we examined baseline characteristics by simple t tests or, in the case of categorical data, with exact tests."
225,PMC3028347,S109,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,reports of adverse events were also examined by exact tests.
226,PMC3028347,S111,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Funding and role of the sponsor.,"the intramural research programs of nichd and national institute of diabetes and digestive and kidney diseases (niddk), nih, and the national center on minority health and health disparities (ncmhd), nih, which funded the study, had no role in study design, data accrual, data analysis, or manuscript preparation."
227,PMC3028347,S112,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Funding and role of the sponsor.,"the authors designed the study, wrote and made the decision to submit the manuscript for publication, and affirmed the completeness, accuracy, and integrity of the data and data analyses."
228,PMC3028347,S113,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Funding and role of the sponsor.,"monitoring of the study, measurement and adjudication of study end points, and statistical analyses were performed by the authors without sponsor involvement."
229,PMC3028347,S114,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Funding and role of the sponsor.,the manuscript was drafted by the principal investigator and revised by the coauthors.
230,PMC3028347,S36,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study sample.,"obese children, aged 6–12 years, recruited through newspaper advertisements and letters to physicians, were eligible if they had bmi ≥95th percentile according to the centers for disease control and prevention 2000 growth charts for the united states; were prepubertal or early pubertal (defined as breast tanner stage i–iii for girls; testes <8 ml for boys); and had fasting hyperinsulinemia, defined as fasting insulin ≥15 μu/ml, the 99th percentile for fasting insulin among 224 nonobese 6- to 12-year-old children studied as outpatients at the national institutes of health (nih) with the same insulin assay (unpublished data)."
231,PMC3028347,S37,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study sample.,this cut point is also consistent with some prior adult data (41).
232,PMC3028347,S38,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study sample.,"children were excluded if they had impaired fasting glucose, were diabetic, or reported a diagnosed renal, cardiac, endocrine, pulmonary, or hepatic disease that might alter body weight."
233,PMC3028347,S39,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study sample.,subjects were excluded for baseline creatinine >1 mg/dl and for alanine aminotransferase (alt) or aspartate aminotransferase (ast) that exceeded 1.5 times the upper limit of the laboratory normal range.
234,PMC3028347,S40,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study sample.,"the study was approved by the institutional review boards of the eunice kennedy shriver national institute of child health and human development (nichd), nih, and the phoenix area indian health service."
235,PMC3028347,S41,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study sample.,written assent and consent were obtained from children and their parents.
236,PMC3028347,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study sample.,the study was overseen by a data and safety monitoring board convened by nichd.
237,PMC3028347,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Design overview.,we conducted a single-center trial from september 2000 to august 2008.
238,PMC3028347,S45,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Design overview.,"after an outpatient screening visit, participants were admitted as inpatients to the nih clinical research center (crc) for assessment and then entered a 6-month randomized placebo-controlled double-blind treatment period and were then readmitted for reassessment."
239,PMC3028347,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Design overview.,participants who completed the randomized phase were offered an additional 6 months of open-label metformin.
240,PMC3028347,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,"we randomly assigned participants in a 1:1 randomization ratio to receive metformin hydrochloride or placebo, twice daily with meals."
241,PMC3028347,S49,['8a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Randomization and interventions.,"investigators assigned consecutive code numbers to participants from prespecified lists stratified by race/ethnicity, sex, and degree of pubertal development."
242,PMC3028347,S50,"['8b', '11b', '8a']","[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Randomization and interventions.,the crc pharmaceutical development section used permuted blocks with stratification to generate allocations that translated code numbers into study group assignments by using a pseudo-random number program and prepared identically appearing placebo and metformin (u.s.p.
243,PMC3028347,S51,"['11b', '8b', '8a']","[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Randomization and interventions.,"grade; sst corporation, clifton, nj) capsules (250 mg/capsule)."
244,PMC3028347,S52,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Randomization and interventions.,pharmacy personnel not involved with the conduct of the study dispensed study capsules in containers that differed only by participant code number.
245,PMC3028347,S53,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,"no participant, investigator, or other medical or nursing staff interacting with participants was aware of study group assignments during the trial."
246,PMC3028347,S54,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,"once baseline assessments were completed, subject’s study medication dose was progressively increased according to a prespecified algorithm over a 3-week period, starting with 500 mg twice daily and increasing to a maximum dose of 1,000 mg twice daily."
247,PMC3028347,S55,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,the typical adult maximum dose was selected as the goal because the weight of the severely obese participants to be enrolled (table 1) was anticipated to be similar to that of adults.
248,PMC3028347,S56,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,we decreased the dose by 250 mg/dose for 1 week when participants reported difficulty tolerating study medication and then attempted to increase it.
249,PMC3028347,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,study medication dose was progressively lowered by 250 mg/day if a prescribed dosage could not be tolerated after a 7-day trial.
250,PMC3028347,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,"once a tolerated dose was found, attempts were made to increase the dosage prescribed."
251,PMC3028347,S59,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,study medication was discontinued if 250 mg/day was not tolerated.
252,PMC3028347,S60,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,a daily chewable multivitamin (flintstones complete) containing 6 μg cyanocobalamin was also prescribed.
253,PMC3028347,S61,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,"after conclusion of the randomized phase, participants were prescribed increasing doses of commercially available metformin in two divided doses with a maximum dose of 2,000 mg/day plus a daily multivitamin for an additional 6 months."
254,PMC3028347,S62,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,"table 1 baseline participant characteristics          during both study phases, each participant and a parent/guardian met monthly with a dietitian who administered a weight-reduction lifestyle modification program that promoted a reduced-energy diet, increased physical activity, and decreased inactivity."
255,PMC3028347,S63,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,participants were trained to complete a baseline 7-day food diary that was reviewed by a registered dietitian.
256,PMC3028347,S64,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,these data were used to offer individualized prescriptions for a “traffic light” style (42) 500 kcal/day–deficit diet that reduced fat and energy intake.
257,PMC3028347,S65,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,the exercise prescription consisted of encouraging 30 min of aerobic exercise every day and inclusion of lifestyle exercise whenever possible and was monitored by pedometer readings recorded by parents.
258,PMC3028347,S66,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomization and interventions.,"adherence was gauged through self-monitoring of medication taken, food eaten, activity performed, amount of inactive time, and pedometer readings recorded in a progress book that was reviewed monthly."
259,PMC3028347,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,"subjects who met inclusion criteria were admitted as inpatients to the crc for the following measurements: weight in a hospital gown using a calibrated digital scale (life measurement instruments, concord, ca); height in triplicate using a stadiometer (holtain, crymych, u.k.) calibrated before each measurement; abdominal and hip circumferences (assessed in triplicate) and triceps skinfold thickness (lange calipers; cambridge scientific industries, cambridge, md) by trained research dietitians (c.g.s. and n.g.s.); blood pressure using an automated sphygmomanometer (dinamap-plus; critikon, tampa, fl) measured in the seated position after at least 5 min rest; a hand roentgenogram for determination of skeletal age; whole-body fat mass by dual-energy x-ray absorptiometry (dexa) (4500a; hologic, bedford, ma; software version 11.2) and by air displacement plethysmography; and intra-abdominal and subcutaneous abdominal adipose tissue by magnetic resonance imaging at l2–l3 and l4–l5 (t1-weighted spin-echo images, 0.5 t, relaxation time 400 ms, time of excitation 10 ms, number of repetitions of excitations 10)."
260,PMC3028347,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,a 2-h hyperglycemic (200 mg/dl) clamp was also performed at baseline and follow-up admissions to estimate insulin sensitivity and first-phase insulin secretion as previously described (43).
261,PMC3028347,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,first-phase insulin was calculated as the mean of measurements obtained during the first 15 min.
262,PMC3028347,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,"whole-body glucose uptake (metabolic rate: m) was defined as the infusion rate of exogenous glucose administered, corrected for urinary glucose losses and the glucose space correction."
263,PMC3028347,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,as a measure of insulin sensitivity (siclamp) the ratio of metabolic rate to steady-state insulin (m/i) was calculated.
264,PMC3028347,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,"at baseline and follow-up, samples obtained in the fasted state were collected for measurement of alt, ast, total and hdl cholesterol, direct ldl cholesterol, and triglycerides (synchron lx20; beckman coulter, fullerton, ca)."
265,PMC3028347,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,"plasma for glucose was collected in tubes containing powdered sodium fluoride and measured by the nih crc clinical laboratory using a roche diagnostics (indianapolis, in) analyzer."
266,PMC3028347,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,c-reactive protein was measured by a high-sensitivity assay (immage immunochemistry systems; beckman coulter) with sensitivity of 0.020 mg/dl.
267,PMC3028347,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,"vitamin b12 and insulin were measured by chemiluminescent immunoassays using siemens healthcare diagnostics (los angeles, ca) immulite instruments."
268,PMC3028347,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,fasting samples were used to estimate insulin resistance by the homeostasis model assessment–insulin resistance (homa-ir) index = insulin (μu/ml) × [glucose (mmol/l)/22.5].
269,PMC3028347,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,"diagnosis of pediatric metabolic syndrome was made when three or more components were present from among the following: waist circumference, blood pressure, and triglycerides ≥90th percentile for age and sex; hdl cholesterol ≤10th percentile for age and sex; and fasting glucose ≥100 mg/dl (44)."
270,PMC3028347,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Initial assessment.,subjects and parents were also interviewed by a clinical pharmacist who used a structured questionnaire containing a comprehensive list of symptoms designed to identify potential adverse drug reactions (45).
271,PMC3028347,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and follow-up measures.,"the prespecified primary study end point was change in bmi sd score (bmi z), as determined at the end of the 6-month randomized treatment phase."
272,PMC3028347,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and follow-up measures.,"secondary outcomes were changes in bmi, body weight, and fat mass at the conclusion of the randomized phase."
273,PMC3028347,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and follow-up measures.,"tertiary outcomes included changes in skinfold thickness, body circumferences, visceral adipose tissue, insulin resistance, and laboratory components of the metabolic syndrome."
274,PMC3028347,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes and follow-up measures.,participants were seen monthly and exchanged their unused study medication for a new supply at each visit.
275,PMC3028347,S85,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes and follow-up measures.,we used the tally of returned capsules to assess adherence.
276,PMC3028347,S86,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and follow-up measures.,"measurements of bmi, blood pressure, liver function, plasma lactate, and serum vitamin b12 were obtained at each visit, along with an interim history obtained using a structured list of queries."
277,PMC3028347,S87,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Outcomes and follow-up measures.,"after 6 months of treatment, subjects were re-evaluated and then offered open-label metformin for a second 6-month treatment period with continued monthly visits."
278,PMC3028347,S89,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis.,power was based on prior data we collected examining bmi change over 6 months in obese 6- to 11-year-old children with hyperinsulinemia.
279,PMC3028347,S90,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis.,"we calculated that among severely obese children, a total sample size of 60 participants would detect a between-group difference of 0.09 bmi sd score units (approximately equivalent to a 2 kg/m2 difference) with 80% power."
280,PMC3028347,S91,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis.,participant accrual was set at 100 participants to allow as much as 40% loss to follow-up (46).
281,PMC3028347,S92,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"the reported primary data analyses were prespecified and analyzed using spss for windows, version 14.0 (spss, chicago, il)."
282,PMC3028347,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,interim analyses for efficacy were performed by the data safety monitoring board when 40 and 70 subjects had been enrolled for 6 months of randomized phase treatment.
283,PMC3028347,S94,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"using the lan-demets implementation of the o’brien-fleming method, the critical two-tailed α values were defined for each look, such that a p value of 0.04515 was considered significant at the end of the study."
284,PMC3028347,S95,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,we assessed efficacy in the intention-to-treat sample of all randomly assigned participants using a multiple imputation model for missing data under a missing-at-random assumption.
285,PMC3028347,S96,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"by using norm, version 2.03 (pennsylvania state university, state university park, pa), we included all available baseline and follow-up measures in an imputation model."
286,PMC3028347,S97,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"the imputation datasets were obtained using a sequential chain of 1,200 iterations using initial parameter estimates supplied by running the expectation-maximization (em) algorithm."
287,PMC3028347,S98,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"starting after the first 200 iterations, data were sampled with 50 iterations between successive imputations."
288,PMC3028347,S99,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis.,"each of the imputation-completed datasets was then analyzed separately using the prespecified ancova model with spss for windows, version 14.0."
289,PMC3036630,S43,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"thirty-two patients with mild to moderately severe copd were included from two respiratory clinics in amsterdam, the netherlands."
290,PMC3036630,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,the definition of copd was based on gold[1].
291,PMC3036630,S45,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"inclusion criteria were symptoms of dyspnea, chronic cough or sputum production, current or ex-smoker with at least 20 packyears of smoking history, postbronchodilator fev1 >1.5 liter and >50% of predicted value, fev1/fvc <0.70 and clinically stable for ≥ 4 weeks prior to recruitment."
292,PMC3036630,S46,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"exclusion criteria were (inhaled) steroid therapy or antibiotic treatment or exacerbation or chest infection ≤ 4 weeks prior to recruitment, treatment with β-blockers, respiratory disease other than copd including known asthma or allergic rhinitis and contra-indications for challenge testing according to international guidelines[15]."
293,PMC3036630,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,patients were asked to withhold strenuous exercise and smoking for 6 hrs and eating for 2 hrs; caffeine and short-acting bronchodilators for 8 hrs; long-acting bronchodilators for 48 hrs; short-acting anti-cholinergics for 24 hrs; long-acting anti-cholinergics and anti-histamines for 72 hrs; and leukotriene antagonists for 4 days prior to the mannitol challenge.
294,PMC3036630,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,the study was approved by the hospital medical ethics committee and all patients gave their written informed consent.
295,PMC3036630,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"the study was registered in the netherlands trial register under ntr 1283, was designed, performed and analysed by the authors, and was not sponsored by others than the academic medical centre, amsterdam, the netherlands itself."
296,PMC3036630,S51,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the study had a cross-sectional design with two studies days comprising randomized challenges with hypertonic saline and mannitol (figure 1).
297,PMC3036630,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"at a separate screening visit, inclusion and exclusion criteria were examined, postbronchodilator (400 μg salbutamol) spirometry was performed and diffusion capacity was measured."
298,PMC3036630,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,figure 1 study design.
299,PMC3036630,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the sequence of the two study visits was randomized [interval (median (range)):7(7-15) days].
300,PMC3036630,S55,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,on one day sputum was induced by hypertonic saline and a venous blood sample was obtained.
301,PMC3036630,S56,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"on the other day exhaled nitric oxide was measured first, followed by assessment of atopy and mannitol challenge testing."
302,PMC3036630,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,"spirometry (masterscreenpneumo; jaeger; würzburg, germany) was performed by a trained respiratory technician according to the latest recommendations[16]."
303,PMC3036630,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,"diffusion capacity of the lung for carbon monoxide (dl, co) was measured according to the recommendations using the single breath method and was corrected for haemoglobin[17]."
304,PMC3036630,S62,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Measurements,"mannitol challenge was performed using a commercially available kit (pharmaxis ltd; sydney, australia) as described by anderson et al[8]."
305,PMC3036630,S63,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Measurements,"patients inhaled sequential doses of 5, 10, 20, 40, 80, 160, 160 and 160 mg of mannitol via the inhaler."
306,PMC3036630,S64,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Measurements,the test stopped when 15% fall in fev1 was achieved or the cumulative dose of 635 mg had been administered.
307,PMC3036630,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,"response-dose-ratio (rdr) was calculated as the%fall in fev1 at the last dose, divided by the total cumulative dose mannitol (%fall.mg) in milligrams administered[18]."
308,PMC3036630,S66,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Measurements,"if a patient had to cough spontaneously during the mannitol challenge, he or she was asked to expectorate."
309,PMC3036630,S67,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Measurements,this sputum was labeled as mannitol-induced sputum.
310,PMC3036630,S69,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Measurements,"prior to sputum induction, patients inhaled 200 μg salbutamol."
311,PMC3036630,S70,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Measurements,sputum was induced by inhalation of nacl 4.5% during 3 × 5 min intervals[19].
312,PMC3036630,S71,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Measurements,this sputum was labeled as induced sputum.
313,PMC3036630,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,whole sputum samples were processed according to a protocol that has been validated in our laboratory[20].
314,PMC3036630,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,differential cell counts were expressed as the percentage of non-squamous cells.
315,PMC3036630,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,absolute cell numbers were calculated as (% cell × total cell count)/sputum weight.
316,PMC3036630,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,sputum samples containing >80% non-squamous cells were excluded from analysis.
317,PMC3036630,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,all sputum cell counts were performed by one experienced and qualified technician blinded to the clinical details.
318,PMC3036630,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,as an extra control 10% of the samples were analyzed by a second technician.
319,PMC3036630,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,"levels of eosinophil cationic protein (ecp; detection limit >60 pg/ml), myeloperoxidase (mpo; detection limit >1.5 ng/ml), interleukin-8 (il-8; detection limit >19.1 pg/ml) and alpha-2-macroglobulin (α2m; detection limit >2.1 mg/ml) were measured by enzyme-linked immunosorbent assays (elisa)[21,22]."
320,PMC3036630,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Measurements,"feno was measured with a portable rapid-response chemoluminescent analyser (flow rate 50 ml/s; niox system, aerocrine, sweden) according to recent guidelines[23]."
321,PMC3036630,S83,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Measurements,the relationship between ahr to mannitol (rdr) and the markers of airway inflammation were analyzed using pearson's correlation coefficient (rp).
322,PMC3036630,S84,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Measurements,non-normally distributed data were log-transformed for further analysis.
323,PMC3036630,S85,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Measurements,"if no cells were counted, a value of 0.1 was taken before log-transformation."
324,PMC3036630,S86,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Measurements,"receiver operating characteristic (roc) curves were constructed, using rdr against eosinophilic vs non eosinophilic copd (threshold 2.5% sputum eosinophils)."
325,PMC3036630,S87,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Measurements,wilcoxon signed rank test and bland-altman analysis was used to compare cell counts of the two sputum samples.
326,PMC3036630,S88,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Measurements,a sample size estimation showed that the detectable value of the correlation (r) under the alternative hypothesis with a sample of 23 patients (n) is between 1-0.55 (power = 0.808; alpha = 0.05).
327,PMC3036630,S89,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Measurements,"therefore, thirty-two patients were recruited taking into account an expected 10% drop-out rate and a 20% probability of missing or non-valid data."
328,PMC3070271,S34,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,this was a multicentre trial including six centres.
329,PMC3070271,S35,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"inclusion criteria were age 2–20 years, a diagnosis of sjia,1 more than 6 months' disease duration, active systemic disease (disease-related fever and/or c-reactive protein (crp) >20 mg/l and/or first hour erythrocyte sedimentation rate (esr) >20) and significant overall disease activity at day 1 (d1) (at least three of the following criteria: (1) physician global assessment of disease activity ≥20/100; (2) parent/patient assessment of disease effect on overall wellbeing ≥20/100; (3) childhood health assessment questionnaire score ≥0.375/3; (4) ≥2 joints with active arthritis; (5) ≥2 joints with non-irreversible limited range of motion and (6) esr ≥30) despite oral prednisone or prednisolone ≥0.3 mg/kg or 10 mg/day (whichever was lower)."
330,PMC3070271,S36,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"female subjects entering the study were prepubescent, sexually inactive or required to use effective contraception."
331,PMC3070271,S37,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,exclusion criteria included previous treatment with an il-1 inhibitor or any condition contraindicating immunosuppressive treatment.
332,PMC3070271,S38,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"intravenous or intra-articular steroids, immunosuppressive drugs and disease-modifying antirheumatic drugs (dmards) had to be stopped at least 1 month before study onset or for longer periods of time depending on their half-life."
333,PMC3070271,S39,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"all patients entering the study, and their parents for patients aged <18, gave written informed consent."
334,PMC3070271,S41,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the study was approved by the local independent ethics committee and consisted of two parts (figure 1).
335,PMC3070271,S42,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"part 1 was a randomised, double-blind, placebo-controlled phase."
336,PMC3070271,S43,"['8a', '5']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 1, 0, 0]",Study design,"at d1, eligible patients were randomised to receive either anakinra or placebo (1:1) from d1 to month 1 (m1) using a computer-generated random list."
337,PMC3070271,S44,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Study design,patients were stratified by centres and randomisation was balanced across treatments and centres.
338,PMC3070271,S45,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Study design,"the randomisation information included the randomisation number, the centre, the assigned treatment and the date of randomisation."
339,PMC3070271,S46,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"investigators, other caregivers, the patients and their parents remained blinded to the assigned treatment."
340,PMC3070271,S47,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,the primary objective was to demonstrate a higher proportion of responders in group 1 than group 2.
341,PMC3070271,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,no immunosuppressive drugs or dmards were allowed during the trial.
342,PMC3070271,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,non-steroidal anti-inflammatory drugs and corticosteroids had to be taken at stable dosage for 1 month before d1 and until m1.
343,PMC3070271,S50,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,figure 1 study design.
344,PMC3070271,S51,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"*measurement of serum amyloid a and ferritin levels, assessment of the percentage of glycosylated ferritin, gene expression profiling analysis and cytokine measurements."
345,PMC3070271,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,†measurement of the concentration of anakinra in plasma (pharmacokinetic analyses).
346,PMC3070271,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,‡measurement of serum anti-pneumococcal antibodies.
347,PMC3070271,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"d, day; m, month."
348,PMC3070271,S55,"['3a', '5']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,part 2 was an open-label treatment period: all patients received anakinra after m1.
349,PMC3070271,S56,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"tapering the dose of corticosteroids was allowed after the m1 visit (reduction of 0.4–0.5 mg/kg monthly for daily doses of ≥1.5 mg/kg, 0.3–0.4 mg/kg for doses between 1 and 1.5 mg/kg, 0.2–0.3 mg/kg between 0.6 and 1 mg/kg, 0.1–0.2 mg/kg between 0.3 and 0.6 mg/kg, ≤0.10 mg/kg for doses <0.3 mg/kg)."
350,PMC3070271,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,"measurement of serum amyloid a (saa) and ferritin levels and the percentage of glycosylated ferritin were performed at d1, m1 and m6."
351,PMC3070271,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,"total ferritin concentration was measured on a dimension rxl hm according to the guidelines of the manufacturer (dade behring, paris, france)."
352,PMC3070271,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,"glycosylated ferritin was determined according to the method of worwood et al,11 with minor modifications as previously described.12"
353,PMC3070271,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,pharmacokinetic (pk) analyses were performed on blood taken at m2 and m6.
354,PMC3070271,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,"concentrations of anakinra in plasma samples were determined using the antibody (ab) elisa purchased from r&d systems (minneapolis, minnesota, usa)."
355,PMC3070271,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,patients who were naive from anti-pneumococcal immunisation received pneumo23 immunisation at d1 in order to assess at m1 and m12 the effect of anakinra treatment on anti-pneumococcal ab response to five capsular polysaccharides.13
356,PMC3070271,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Gene expression profiling and cytokine measurements,"blood samples were collected in tempus tubes (abi, foster city, california, usa) from the patients at d1, m1 and m6 and from age and gender-matched healthy controls."
357,PMC3070271,S66,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Transcriptional module-based analysis,this mining strategy has been described in detail elsewhere.14
358,PMC3070271,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Transcriptional module-based analysis,"in this study, refseq ids were used to match probes between the affymetrix u133 platform, which was used to generate the original set of modules using pbmc expression data,14 and illumina hu6 platform, which was used to hybridise whole blood samples from patients enrolled in this study and healthy controls."
359,PMC3070271,S68,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Transcriptional module-based analysis,unambiguous matches in illumina were found for 2109 out of the 5348 affymetrix probe sets.
360,PMC3070271,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Transcriptional module-based analysis,illumina modules containing <10 genes were not included in the analysis.
361,PMC3070271,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Cytokine multiplex analysis,"serum samples were analysed using the cytokine assay kit (bio-rad, hercules, california, usa) according to the manufacturer's protocol."
362,PMC3070271,S73,"['5', '6a']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0]","Assessment, outcome and safety measures","the primary objective was to compare the efficacy after 1 month's treatment with anakinra (2 mg/kg subcutaneously daily, maximum 100 mg) or placebo in the two groups of patients."
363,PMC3070271,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Assessment, outcome and safety measures","to be responders to a modified american college of rheumatology pediatric (acrpedi) 30 score built for the purpose of the trial, patients had to fulfil the three following conditions: (1) acrpedi 30 response15; (2) absence of disease-related fever (body temperature <38°c over the past 8 days) and (3) 50% decrease compared with d1 or normalisation of both crp and esr values."
364,PMC3070271,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Assessment, outcome and safety measures","modified acrpedi 30, 50, 70 and 100 responses, assessed throughout the study, included an improvement of 30%, 50%, 70% or more and 100% respectively, in at least three of the six core criteria for juvenile rheumatoid arthritis and a worsening of 30 or more in no more than one of the criteria."
365,PMC3070271,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Assessment, outcome and safety measures","the criteria were the physician's global assessment of disease activity and the patient's or the parents' global assessment of overall wellbeing, the number of joints with active arthritis, the number of joints with limited range of motion, the childhood health assessment questionnaire and esr.15"
366,PMC3070271,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Assessment, outcome and safety measures","a disease flare was defined as either (1) a reoccurrence of disease-related fever or any systemic symptom, or (2) an increase by twofold of either the esr or crp value, or (3) a worsening of ≥30% in at least three of the six acrpedi core criteria and an improvement of ≥30% in no more than one of the criteria."
367,PMC3070271,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Assessment, outcome and safety measures","if the number of joints with active arthritis was used as a criterion of flare and the patient initially had no active joints or only one active joint, an increase in the number of joints with active arthritis to at least two was required."
368,PMC3070271,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Assessment, outcome and safety measures","we also aimed to assess the number of patients who reached m6 with inactive disease, as defined by wallace et al16 under a daily dose of predniso(lo)ne <0.3 mg/kg or 10 mg, whichever was lower."
369,PMC3070271,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Assessment, outcome and safety measures",adverse events (aes) were recorded throughout the study.
370,PMC3070271,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Assessment, outcome and safety measures",specific procedures were set up for serious aes (saes).
371,PMC3070271,S82,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]","Assessment, outcome and safety measures",this trial was registered at http://www.clinicaltrials.gov (registration number: nct00339157).
372,PMC3070271,S84,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Data analysis,"we expected at least 60% difference in the percentage of patients obtaining improvement in the anakinra-treated group (group 1) compared with the control group (group 2), with no more than 10% patients improving in group 2."
373,PMC3070271,S85,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Data analysis,"given a 5% type i error, a 20% type ii error and a two-sided fisher exact test, 12 patients per group were required."
374,PMC3070271,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,an intention-to-treat analysis was retained.
375,PMC3070271,S87,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,"to explore whether each variable from the acrpedi score, crp, saa and/or parent/patient assessment of pain were associated with response to treatment, the ratio (value at inclusion − value at m1)/value at inclusion, was compared in both groups."
376,PMC3070271,S88,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,"qualitative and quantitative data were compared using wilcoxon test and fisher exact test, respectively."
377,PMC3070271,S89,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,the r statistical software was used for statistical analysis.
378,PMC3076731,S34,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,members of the british society for paediatric endocrinology and diabetes recruited patients from participating paediatric endocrinology departments in uk hospitals.
379,PMC3076731,S35,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"inclusion criteria for participation of patients were karyotype confirmed turner’s syndrome (all karyotypes were eligible, including mosaic), age 7-13 years, no previous growth hormone treatment or previous treatment in the range 8.3-11.7 mg/m2/week in five to seven injections a week, no previous oxandrolone and oestrogen therapy, and open epiphyses."
380,PMC3076731,S36,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,exclusion criteria were major systemic illness that might affect growth and social or psychological difficulties likely to seriously impair concordance.
381,PMC3076731,S38,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"we devised a double blind, placebo controlled, randomised controlled trial, including two randomisations in a two by two factorial design."
382,PMC3076731,S39,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,figure 1 shows the flow chart of the design and participants.
383,PMC3076731,S40,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"a steering committee (british society for paediatric endocrinology and diabetes clinical trials/audit group) supervised the study, and an independent data and safety monitoring group was established."
384,PMC3076731,S41,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,all participants’ parents gave written informed consent.
385,PMC3076731,S42,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"fig 1 flow chart of participation in uk turner study according to treatment groups, completions, and withdrawals."
386,PMC3076731,S43,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"*withdrawn before 12 years of age (that is, randomised only at randomisation 1 to oxandrolone or placebo)."
387,PMC3076731,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,†aged ≥12.25 years at recruitment; oestrogen treatment started at 14 years with no randomisation.
388,PMC3076731,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"‡withdrawn after 12 years of age (that is, randomised at randomisation 1 to oxandrolone or placebo and at randomisation 2 if oestrogen treatment needed)"
389,PMC3076731,S47,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Randomisation and masking,"the british society for paediatric endocrinology and diabetes clinical trials unit (cambridge, uk) used minimisation by weighted randomisation for the study’s two randomisations.20"
390,PMC3076731,S48,"['10', '5']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"randomisation 1, to oxandrolone or placebo, took place at age 9 years (or at enrolment, if older) and was balanced for enrolling centre, quarter of mid-parental height, and previous exposure to growth hormone treatment."
391,PMC3076731,S49,"['10', '5']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"randomisation 2 took place at age 12 years in girls with ovarian failure (basal serum follicle stimulating hormone concentration >10 u/l), with additional minimisation for randomisation 1, to begin oral ethinylestradiol or placebo at 12 years; the placebo group subsequently started ethinylestradiol at 14 years."
392,PMC3076731,S50,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"girls with a follicle stimulating hormone concentration below 10u/l and a karyotype associated with preservation of ovarian function (45,x/46,xx and 45,x/47,xxx21) (the spontaneous puberty group) were not randomised at randomisation 2."
393,PMC3076731,S51,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,girls with other karyotypes were tested for concentrations of gonadotrophin releasing hormone and were randomised at randomisation 2 if the peak follicle stimulating hormone concentration was above 30 u/l.
394,PMC3076731,S52,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,participants enrolled after the age of 12.25 years and without spontaneous puberty (the late group) started ethinylestradiol at 14 years.
395,PMC3076731,S54,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,all participants received the growth hormone preparation of their choice at 10 mg/m2/week in daily subcutaneous injections.
396,PMC3076731,S55,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,"oral oxandrolone (spa, milan, italy) was given at 0.05 mg/kg/day, with a maximum daily dose of 2.5 mg."
397,PMC3076731,S56,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,"oral ethinylestradiol (ucb pharma, slough, uk) was given daily as follows, regardless of the age at starting: year 1, 2 μg; year 2, 4 μg; year 3, four months each of 6, 8, and 10 μg."
398,PMC3076731,S57,"['5', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,"the code for randomisation 2 was broken at 15 years to allow introduction of progesterone therapy: oral norethisterone (cp pharmaceuticals, wrexham, uk) 5 mg daily for five days each month."
399,PMC3076731,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,treatment with growth hormone and oxandrolone continued until final height was reached.
400,PMC3076731,S59,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,oestrogen/progesterone therapy continued at an adult replacement dose once pubertal induction was completed.
401,PMC3076731,S60,['11b'],"[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Treatment,"white, uncoated, flat bevelled edge placebo tablets (7 and 5 mm in diameter) (essential nutrition, brough, uk) were specially manufactured to match the size, weight, and appearance of oxandrolone 2.5 mg and ethinylestradiol 2 µg tablets respectively."
402,PMC3076731,S61,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Treatment,"the study’s central pharmacy (royal hospital for sick children, glasgow, uk) supplied all tablets in a double blind, placebo controlled fashion; only staff at the british society for paediatric endocrinology and diabetes clinical trials unit and the central distributing pharmacy were not blinded to treatment allocations."
403,PMC3076731,S63,['3b'],"[0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Oxandrolone supplies,"in 2004 and 2008, the sole european manufacturer of oxandrolone 2.5 mg ceased production, resulting in 34 participants in 2004 and 11 in 2008 temporarily suspending active oxandrolone treatment (mean duration: 2004, 52 days; 2008, 163 days)."
404,PMC3076731,S64,['3b'],"[0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Oxandrolone supplies,"in 2008, the decision was taken to terminate the treatment arm forthwith, resulting in eight participants stopping oxandrolone treatment prematurely."
405,PMC3076731,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study procedures,"at clinic visits every four to six months, height was measured with a harpenden stadiometer to the last completed 1 mm and converted to an sd score by using the british 1990 reference.22"
406,PMC3076731,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study procedures,"radiographs of the left wrist were obtained annually, and a single observer (wfp) analysed them for bone age estimation according to the tanner whitehouse ii method.23"
407,PMC3076731,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study procedures,"biochemical analyses followed local protocols, and the results were reported centrally."
408,PMC3076731,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study procedures,"standardised pharmacovigilance procedures were followed, with recording of adverse events or reactions at each visit and subsequent review by the data and safety monitoring group."
409,PMC3076731,S70,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study procedures,"data collection ceased if participants withdrew consent, although we included previously collected data in the analysis."
410,PMC3076731,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical methods,"the primary outcome was final height, defined as height velocity less than 1 cm/year and bone age at least 15.5 years."
411,PMC3076731,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical methods,"secondary outcomes were maximum height (that is, the most recently available height), age of attaining final height, and the three summary growth parameters from the sitar analysis described below."
412,PMC3076731,S74,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical methods,"assuming a standard deviation of 5 cm, we needed 50 girls in each group to detect a difference between groups in mean final height of 2.8 cm with 80% power at 5% significance—a total of 100 patients."
413,PMC3076731,S75,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,the study was not formally powered to detect a significant interaction between the two randomisations.
414,PMC3076731,S76,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"in the event, more than 100 patients were recruited, but fewer than 100 were followed up to final height."
415,PMC3076731,S77,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,we estimated the effects of the two randomisations separately by using multiple regression.
416,PMC3076731,S78,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,we also adjusted randomisation 2 (timing of pubertal induction) for randomisation 1 (oxandrolone) and tested for an interaction.
417,PMC3076731,S79,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"in addition, we applied sitar (superimposition by translation and rotation), a novel method of growth curve analysis, to the data.24"
418,PMC3076731,S80,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"sitar transforms individual growth curves so that they become essentially the same as each other and, when superimposed, define the average summary curve."
419,PMC3076731,S81,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"to achieve this, each individual curve is suitably altered in three distinct ways: the curve is shifted up/down (a measure of the child’s size in cm) and left/right (a measure of growth tempo in years), and the age axis is stretched/squashed (a measure of percentage velocity)."
420,PMC3076731,S82,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"size, tempo, and velocity are thus participant specific random effects summarising how each girl’s curve differs from the average curve."
421,PMC3076731,S83,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,the effects of the randomisations can be explored by comparing the values of the random effects by trial arm.
422,PMC3076731,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"equally, separate summary curves can be constructed for each trial arm."
423,PMC3103669,S39,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"this was a 24-week, dose-ranging, multicentre, double-blind, double-dummy, active-controlled study and was approved by all responsible independent ethics committees."
424,PMC3103669,S40,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"the study was performed in accordance with the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ich) harmonised tripartite guidelines for good clinical practice and the ethical principles laid down in the declaration of helsinki, and all patients provided written informed consent."
425,PMC3103669,S41,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the trial was registered with http://www.clinicaltrials.gov (registration number: nct00819585).
426,PMC3103669,S42,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,"at screening, patients indicated which of their joints was most affected by previous gouty arthritis flares."
427,PMC3103669,S43,"['5', '8b']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 1, 0]",Study design,"eligible patients were subsequently randomised 1:1:1:1:1:1:2 to receive a single dose of canakinumab, 25 mg, 50 mg, 100 mg, 200 mg, or 300 mg on day 1, or four canakinumab doses administered at 4-weekly intervals (50 mg on day 1 and at week 4, and 25 mg at weeks 8 and 12), or daily oral doses of colchicine 0.5 mg given for 16 weeks."
428,PMC3103669,S44,"['11a', '11b']","[0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"in order to achieve blinding for patients and investigators, all patients received subcutaneous injections of canakinumab or canakinumab placebo on day 1, and at weeks 4, 8 and 12, and took capsules of colchicine or colchicine placebo daily for 16 weeks (see supplementary material for details)."
429,PMC3103669,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,patients were followed for 24 weeks.
430,PMC3103669,S46,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,allopurinol treatment (100–300 mg) was initiated at baseline or within 1 month before baseline and was administered to all randomised patients once daily for 24 weeks (see supplementary material for details).
431,PMC3103669,S47,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,patients could receive rescue medication as needed (see supplementary material for details).
432,PMC3103669,S49,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"inclusion criteria were: age 18–80 years, diagnosis of gouty arthritis as defined by the american college of rheumatology 1977 preliminary criteria,29 having had at least two gouty arthritis flares in the previous year, body mass index (bmi) of ≤40 kg/m2 and willingness to initiate allopurinol treatment or having initiated allopurinol treatment within 1 month of screening."
433,PMC3103669,S50,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"key exclusion criteria were: having a gouty arthritis flare within 2 weeks of screening, present at screening, or having pain associated with a flare at screening; history of allergy, contraindication, or intolerance to allopurinol or colchicine (see supplementary material for further details)."
434,PMC3103669,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,flares were patient reported.
435,PMC3103669,S53,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"for each flare, patients recorded in a diary the start date, the most affected joint on that day and the severity of pain (see supplementary material for further details)."
436,PMC3103669,S54,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,patients also recorded rescue medication use and pain for at least 7 days after the onset of the flare or longer if the flares persisted for more than 7 days.
437,PMC3103669,S55,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"safety assessments were performed at scheduled visits (2, 4, 8, 12, 16, 20 and 24 weeks) and included collection of blood samples for assessment of the inflammatory marker, c reactive protein (crp), haematology and immunogenicity (at baseline and weeks 8, 16 and 24) and doctor's assessments of local tolerability at sites of subcutaneous injections."
438,PMC3103669,S56,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,adverse events (aes) were reported throughout the study.
439,PMC3103669,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"the primary outcome was determination of the canakinumab dose producing equivalent efficacy to that achieved with colchicine 0.5 mg, with respect to the mean number of flares per patient occurring within 16 weeks post randomisation (ie, the target dose)."
440,PMC3103669,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"secondary efficacy outcomes included: mean number of flares per patient, proportion of patients with at least one flare, time to first flare, average duration of flares and crp levels (see supplementary material for further details)."
441,PMC3103669,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"safety variables included the incidence of aes, serious aes (saes) and infectious aes, the incidence and severity of injection-site reactions, and immunogenicity."
442,PMC3103669,S61,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size determination and statistical analysis,a sample size of 350 patients (50 patients in each of the 5 canakinumab single-dose groups and 100 patients in the colchicine group) was considered sufficient to give a 95% confidence interval (ci) of the target dose with reasonable precision.
443,PMC3103669,S62,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size determination and statistical analysis,in order to increase the precision of the analysis the planned total sample size of 400 was increased to approximately 440 patients (see supplementary material for more details).
444,PMC3103669,S63,"['6a', '7b']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0]",Sample size determination and statistical analysis,a preplanned interim analysis was performed when 200 patients had completed 16 weeks.
445,PMC3103669,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Sample size determination and statistical analysis,efficacy and safety analyses were then performed when all patients had completed the study (24 weeks).
446,PMC3103669,S65,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size determination and statistical analysis,"for determination of the primary outcome, the number of flares per patient during 16 weeks was modelled using a negative binomial distribution and a common overdispersion (variance divided by expectation minus 1) for all treatment arms (see supplementary material for more details)."
447,PMC3103669,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Sample size determination and statistical analysis,the main secondary outcome was the mean number of flares per patient at 16 weeks.
448,PMC3103669,S67,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size determination and statistical analysis,"data were analysed according to an analysis of covariance (ancova) with treatment group, allopurinol dose at baseline and bmi at baseline as covariates."
449,PMC3103669,S68,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size determination and statistical analysis,"however, as the distribution of flares per patient was observed to be skewed, the preplanned ancova was considered inappropriate for these data."
450,PMC3103669,S69,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size determination and statistical analysis,"therefore a post hoc analysis using a negative binomial model with treatment group, allopurinol dose at baseline and bmi at baseline as covariates and log (time on study) as an offset was performed with an adjustment made for multiplicity (see supplementary material for further details of analyses for secondary outcomes)."
451,PMC3109952,S38,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"this multicentre, two arm, randomised, controlled, open trial was carried out in 13 centres in the united kingdom and one in the republic of ireland."
452,PMC3109952,S40,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population,"participants were eligible for the study if they were aged 12 years or over and had a plantar wart (verruca) that, in the opinion of a healthcare professional, was suitable for treatment with both salicylic acid and cryotherapy."
453,PMC3109952,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population,"participants were excluded from the study if they had impaired healing (such as from diabetes or peripheral vascular disease); were immunosuppressed (such as agammaglobulinaemia) or were taking immunosuppressant drugs (such as oral corticosteroids); had neuropathy; were receiving renal dialysis; had cold intolerance (such as raynaud’s syndrome or cold urticaria); had any of the following conditions (blood dyscrasias of unknown origin, cryoglobulinaemia, cryofibrinogenaemia, collagen or autoimmune disease); were unable to give informed consent; or were currently in a trial evaluating other treatments for their plantar wart."
454,PMC3109952,S43,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation of participants,"participants were recruited between november 2006 and january 2010 (end of extended recruitment period) from university podiatry school clinics, nhs podiatry clinics, and primary care."
455,PMC3109952,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation of participants,eligible participants gave written informed consent.
456,PMC3109952,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation of participants,they were then randomised equally to receive cryotherapy with liquid nitrogen or daily self treatment with an over the counter 50% salicylic acid treatment.
457,PMC3109952,S46,"['9', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Recruitment and randomisation of participants,"randomisation was performed by a member of the research team either telephoning an independent, secure, remote, telephone randomisation service (york trials unit) or accessing a secure online web randomisation programme, thereby concealing treatment allocation until the moment of randomisation."
458,PMC3109952,S47,"['8b', '8a']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Recruitment and randomisation of participants,"randomisation was simple (that is, it was not restricted in any way such as by stratification or blocked allocation with the allocation sequence being computer generated)."
459,PMC3109952,S50,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,participants randomised to cryotherapy with liquid nitrogen received a maximum of four treatments given two to three weeks apart by a healthcare professional.
460,PMC3109952,S51,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,the liquid nitrogen was applied with a spray (method of choice if available) or a probe.
461,PMC3109952,S52,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,"the treatment was delivered according to the site’s usual practice (such as debridement before treatment, masking of the surrounding area, and padding after treatment)."
462,PMC3109952,S53,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,"on advice from the trial steering committee, sites were advised that the first treatment should be a “gentle freeze” in order to ensure the participant could tolerate the treatment."
463,PMC3109952,S55,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,"participants randomised to self treatment with 50% salicylic acid (verrugon, william ransom and son) were instructed how to apply the treatment according to the manufacturer’s instructions by the treating healthcare professional."
464,PMC3109952,S56,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,patients were directed to fix the adhesive ring with the hole over the verruca and to squeeze a little ointment into the hole and directly on to the verruca.
465,PMC3109952,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,the backing paper from the plaster was then removed and the plaster applied to cover the ring completely.
466,PMC3109952,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,the plaster was then sealed into position.
467,PMC3109952,S59,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,the treatment was repeated daily after gently pumicing or filing off the dead part of the verruca for a maximum of eight weeks.
468,PMC3109952,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measurements,the primary outcome was complete clearance of all plantar warts at 12 weeks after randomisation.
469,PMC3109952,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measurements,clearance of plantar wart was defined as the restoration of normal skin on close inspection.
470,PMC3109952,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measurements,digital photographs of the plantar wart(s) were taken at baseline and at the outcome assessment.
471,PMC3109952,S65,"['6a', '11a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measurements,the photographs were assessed by two assessors who were blind to treatment allocation.
472,PMC3109952,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measurements,they independently assessed the photographs for each participant to determine whether the plantar wart had cleared.
473,PMC3109952,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measurements,any discrepancies were referred to a third assessor.
474,PMC3109952,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measurements,"if no photographs were available for a participant, however, then the blinded outcome assessment undertaken at the site was used."
475,PMC3109952,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measurements,"if neither of these were available for a participant, the patient’s self reported outcome recorded in the week 12 patient questionnaire or on the “verrucae gone form” was used."
476,PMC3109952,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measurements,"secondary outcomes included (a) complete clearance of all plantar warts at 12 weeks after controlling for age, whether the plantar wart had been treated previously, and type of wart and (b) a second model to explore the effect of patient preferences, (c) with clearance of plantar wart at six months, (d) number of warts at 12 weeks, (e) time to clearance of wart, (f) patient satisfaction with the treatment, and (g) adverse events."
477,PMC3109952,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measurements,"questionnaires were administered by post or were completed on line at one, three, and 12 weeks and six months."
478,PMC3109952,S74,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size,"the cochrane systematic review found only one small trial directly comparing the effectiveness of a chemical treatment, salicylic acid, with cryotherapy in patients with warts on their feet alone.6"
479,PMC3109952,S75,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size,"this poor quality study found a 58% cure rate among the patients allocated to cryotherapy, compared with 41% among those treated with salicylic acid."
480,PMC3109952,S76,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size,this difference of 17% was not statistically significant.
481,PMC3109952,S77,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size,"the overall cure rates from this study are smaller than those observed in two placebo controlled trials of salicylic acid, both of which reported cure rates of 85% for active treatment, possibly because more resistant verrucae were included in the study comparing cryotherapy with salicylic acid."
482,PMC3109952,S78,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size,this trial was a superiority study of cryotherapy compared with salicylic acid and was powered to show a 15% difference in effectiveness.
483,PMC3109952,S79,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"in order to give 80% power (5% two sided significance) to show a difference in cure rates of 70% for salicylic acid versus 85% for cryotherapy at 12 weeks, a sample size of 120 patients in each treatment group was required, or 133 patients in each group after allowing for 10% attrition (266 patients in total)."
484,PMC3109952,S81,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all analyses were conducted on an intention to treat basis, including all patients in the groups to which they were randomised."
485,PMC3109952,S82,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"analyses were conducted in sas version 9.2 (sas institute, nc, usa) and spss version 17.0.2 (spss) using two sided significance tests at the 5% significance level for the primary outcome measure and 1% significance level for secondary outcome measures."
486,PMC3109952,S84,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the primary analysis compared the clearance rate of all plantar warts at 12 weeks between the two randomised groups using a χ2 test.
487,PMC3109952,S85,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,cohen’s κ measure of inter-rater agreement was used to assess agreement between the two assessors of the photographs for clearance.
488,PMC3109952,S87,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"a logistic regression model was used to adjust the primary analysis for important prognostic variables (age, whether the plantar wart had been previously treated, and type of wart)."
489,PMC3109952,S88,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we also extended the primary outcome model to explore the effect of patient preferences by including preference and an interaction term between preferred treatment and randomised treatment.
490,PMC3109952,S89,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the complete clearance of all plantar warts at six months was analysed in the same way as the primary outcome with adjustments for the same covariates.
491,PMC3109952,S90,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we used negative binomial regression to compare the number of plantar warts at 12 weeks between the two treatment groups with adjustment for the number of plantar warts at baseline.
492,PMC3109952,S91,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,these models are used to estimate the number of occurrences of an event when the event has poisson variation with over-dispersion.
493,PMC3109952,S92,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"the time to clearance of plantar warts was derived as the number of days from randomisation until the date of clearance, as detailed from the participant’s self reported questionnaire."
494,PMC3109952,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"participants whose plantar warts had not cleared were treated as censored, and we calculated their duration in the trial from their date of trial exit, date of last available assessment, or the 183 days to trial cessation, as appropriate."
495,PMC3109952,S94,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,a cox proportional hazards model was used to compare the time to clearance of plantar warts between the two groups adjusting for the same covariates as for the primary outcome.
496,PMC3109952,S95,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the cox proportional hazard assumption was tested globally by the correlation of schoenfeld residuals and survival time (or ranked survival time) and separately for each covariate through the correlation of schoenfeld scaled residuals and survival time (or ranked survival time).
497,PMC3109952,S96,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,non-significant correlation indicates that there is not enough evidence that the proportional hazard assumption has been violated.
498,PMC3109952,S97,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,data on patient satisfaction with the treatment and adverse events were summarised by treatment group but no statistical analyses were performed.
499,PMC3128457,S101,['11b'],"[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Blinding,tranexamic acid and placebo ampoules were indistinguishable.
500,PMC3128457,S102,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Blinding,"tranexamic acid was manufactured by pharmacia (pfizer, sandwich, uk) and placebo by st mary’s pharmaceutical unit, cardiff, uk."
501,PMC3128457,S103,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Blinding,"the treatment packs were prepared by an independent clinical trial supply company (bilcare, crickhowell, uk)."
502,PMC3128457,S104,['11b'],"[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Blinding,correct blinding and coding of ampoules was assured by independent random testing of each batch by high performance liquid chromatography to confirm the contents.
503,PMC3128457,S106,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,we assessed the intra-observer reliability of haemorrhage measurements using the intra-class correlation coefficient.
504,PMC3128457,S107,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,we assessed the reliability of binary measurements with the κ statistic.
505,PMC3128457,S108,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"for continuous variables measuring the haemorrhage, we used the average measurement of the two independent readings in all analyses."
506,PMC3128457,S109,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"for binary variables, we considered an intracranial finding to be present only if it was reported as present on both readings of a particular patient’s brain scan."
507,PMC3128457,S110,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,we used generalised linear models adjusted for baseline variables.
508,PMC3128457,S111,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,covariates included in the adjustment were glasgow coma scale and age.
509,PMC3128457,S112,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"for computed tomography outcomes, we also adjusted for time from injury to first and second scan and for initial haemorrhage volume."
510,PMC3128457,S113,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,in our analysis of mass effect we adjusted for initial mass effect.
511,PMC3128457,S114,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"adjusted effects are considered in the primary analysis, but both adjusted and unadjusted effect measures are reported."
512,PMC3128457,S115,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,we reported 95% confidence intervals for all the effects estimated and p values for the adjusted analyses.
513,PMC3128457,S116,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"haemorrhage growth was analysed using multiple linear regression (analysis of covariance), the main factor being the treatment group."
514,PMC3128457,S117,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,outcomes are reported combined and separately for patients who did or did not undergo neurosurgical evacuation between the first and second computed tomography scan.
515,PMC3128457,S118,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,binary outcomes were analysed using logistic regression.
516,PMC3128457,S119,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,subarachnoid haemorrhage scale was compared in the two groups using a non-parametric rank test (kruskal-wallis).
517,PMC3128457,S120,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,all analyses were undertaken on an intention to treat basis.
518,PMC3128457,S121,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"to evaluate the clinical relevance of the primary surrogate outcome selected in this study, we also analysed the clinical effect of haemorrhage growth."
519,PMC3128457,S122,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"we conducted a logistic regression analysis with dependency (as defined by the modified oxford handicap scale) as the outcome and haemorrhage growth as the main exposure variable, with adjustment by the potential confounders of initial haemorrhage volume, glasgow coma scale, age, time from injury to computed tomography, and treatment."
520,PMC3128457,S123,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,we used the statistical software package stata (version se/11·0) from statacorp.
521,PMC3128457,S125,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,"the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report."
522,PMC3128457,S126,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,the writing committee had full access to all data in the study and had final responsibility for the decision to submit for publication.
523,PMC3128457,S39,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"trial design—this double blind, randomised, placebo controlled trial was nested in a cohort of crash-2 trial participants."
524,PMC3128457,S40,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"the aims, methods, and results of the crash-2 trial are presented in detail elsewhere.2"
525,PMC3128457,S41,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,participants—the trial was conducted in a cohort of crash-2 trial participants.
526,PMC3128457,S42,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"patients eligible for inclusion in the intracranial bleeding study fulfilled the inclusion criteria for the crash-2 trial—adult trauma patients with significant haemorrhage (systolic blood pressure <90 mm hg or heart rate >110 beats per min, or both) or who were considered to be at risk of significant haemorrhage, and who were within 8 hours of injury (study entry governed by the uncertainty principle)11—but they also had traumatic brain injury (glasgow coma scale ≤14 and a brain computed tomography compatible with traumatic brain injury)."
527,PMC3128457,S43,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,pregnant women and patients for whom a second brain scan was not possible were excluded.
528,PMC3128457,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,consent procedures at participating hospitals were established by local regulation and the appropriate ethics committees.
529,PMC3128457,S45,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,study settings—patients were recruited from 10 hospitals in india and colombia.
530,PMC3128457,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"the sites were selected according to their interest in the topic, adequate facilities for conducting computed tomography, and expected recruitment rate."
531,PMC3128457,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Interventions,"participants were randomly allocated to receive a loading dose of 1 g tranexamic acid infused over 10 minutes, followed by an intravenous infusion of 1 g over eight hours, or matching placebo (sodium chloride 0.9%)."
532,PMC3128457,S50,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"we obtained two brain computed tomograms for each participant, the first before randomisation and the second 24–48 hours later."
533,PMC3128457,S51,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,a neuroradiologist (zoe morris) who was blind to treatment allocation and clinical findings evaluated the first and second scans.
534,PMC3128457,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"readings of the two scans were done twice (with the second reading blind to the results of the first reading) by central reading of the electronic dicom image files in digital jacket software (desacc, chicago il, usa)."
535,PMC3128457,S53,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"the size of intra-parenchymal haemorrhages, haemorrhagic contusions, subdural epidural haematomas, subarachnoid haemorrhage, ischaemic lesions; mass effect; and the overall amount of tissue damage were assessed with validated rating scales based on previous work (see box).12 13 14 15 16"
536,PMC3128457,S54,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the individual ratings and measurements were recorded on a rating form developed for the purposes of this study (shown in appendix on bmj.com).
537,PMC3128457,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,measurement—a representative slice at the centre of the haematoma was selected.
538,PMC3128457,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the maximum linear length (a) in cm was multiplied by the maximum width perpendicular to a (b) and the maximum depth (c) in cm.
539,PMC3128457,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the depth (c) was determined by multiplying the number of slices on which haematoma is visible by the slice interval thickness listed on the ct scan.
540,PMC3128457,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,to obtain the volume in cm3 the final product (a.b.c) was divided by 2
541,PMC3128457,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,measurement—a representative slice near the centre of the haematoma was selected.
542,PMC3128457,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the linear distance in cm between each corner of the subdural crescent was used to determine the length (a).
543,PMC3128457,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the width (b) was measured as the maximum thickness in cm of haematoma from the inner table of the skull perpendicular to the length.
544,PMC3128457,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the depth (c) was determined by multiplying the number of slices on which haematoma is visible by the slice interval thickness listed on the ct scan.
545,PMC3128457,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,to obtain the volume in cm3 the final product (a.b.c) was divided by 2.
546,PMC3128457,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,measurement—a representative slice near the centre of the haematoma was selected.
547,PMC3128457,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the linear distance in cm between each corner of the epidural lens shape was used to determine the length (a).
548,PMC3128457,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the width (b) was measured as the maximum thickness in cm of haematoma (b) from the inner table of the skull perpendicular to the length.
549,PMC3128457,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the depth (c) was determined by multiplying the number of slices on which haematoma is visible by the slice interval listed on the ct scan.
550,PMC3128457,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"to obtain the volume in cm3, the final product (a.b.c) was divided by 2"
551,PMC3128457,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,measurement—blood within subarachnoid spaces between pia and arachnoid membranes.
552,PMC3128457,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,haemorrhage thickness was categorised as ≤5 mm or >5 mm.
553,PMC3128457,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the thickness was rated within a representative sulcus
554,PMC3128457,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,measurement—focal low attenuation in distribution indicating arterial ischaemic cause rather than traumatic contusional injury rated according to validated scale for ischaemic stroke
555,PMC3128457,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"measurement—(1) sulcal effacement, (2) ventricular effacement, (3) uncal herniation, (4) cisterns compressed, (5) cisterns absent, (6) midline shift (in mm)"
556,PMC3128457,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"the primary outcome was total haemorrhage growth, defined as the difference in the combined volume (ml) of all intracranial haemorrhagic lesions (intra-parenchymal haematoma + haemorrhagic contusion + subdural haematoma + epidural haematoma) from the first to the second scan."
557,PMC3128457,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"secondary outcomes were (a) significant haemorrhage growth defined as an increase by ≥25% of total haemorrhage in relation to its initial volume, (b) new intracranial haemorrhage (apparent on the second scan but not apparent on the first), (c) change in subarachnoid haemorrhage grade, (d) mass effect, and (e) new focal cerebral ischaemic lesions (apparent on the second scan but not the first)."
558,PMC3128457,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"the clinical outcomes were death from any cause, dependency, and the need for neurosurgical intervention."
559,PMC3128457,S84,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"clinical outcomes were recorded at hospital discharge, at 28 days after randomisation, or death, whichever occurred first."
560,PMC3128457,S85,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,dependency was measured using the five point modified oxford handicap scale (mohs).17
561,PMC3128457,S86,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"we dichotomised the scale into “dependent” (fully dependent requiring attention day and night, or dependent but not requiring constant attention) or “independent” (some restriction in lifestyle but independent, minor symptoms, or no symptoms)."
562,PMC3128457,S87,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"we also reported a “composite poor outcome” defined as a patient who developed one or more of the following during the follow-up period—significant haemorrhage growth, new intracranial haemorrhage, new focal cerebral ischaemic lesions, the need for neurosurgery, or death."
563,PMC3128457,S88,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"adverse events that were serious, unexpected, and suspected to be related to the study treatment were reported separately."
564,PMC3128457,S90,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"assuming an initial intracranial haemorrhage volume of 20 ml, an average haemorrhage growth of 7 ml in the control group and a correlation of 0.6 between initial and follow-up volumes, we estimated that a trial with 300 patients would have 80% power (α=0.05) to detect a 35% reduction in haemorrhage growth."
565,PMC3128457,S91,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"we pre-specified in the protocol that, as this study was nested within the main crash-2 trial, even if the planned sample size of 300 patients was not achieved, recruitment would stop at the same time as the main crash-2 trial."
566,PMC3128457,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,"after eligibility had been confirmed and the locally approved consent procedures had been completed, patients were randomly assigned."
567,PMC3128457,S94,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Randomisation,"randomisation was balanced by centre, with an allocation sequence based on a block size of eight."
568,PMC3128457,S95,['8a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Randomisation,we used a local pack system that selected the lowest numbered treatment pack from a box containing eight numbered packs.
569,PMC3128457,S96,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Randomisation,"apart from the pack number, the treatment packs were identical."
570,PMC3128457,S97,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,"the pack number was recorded on the entry form, which was sent to the international trial coordinating centre in london, uk."
571,PMC3128457,S98,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,"once the treatment pack number was recorded, the patient was included in the trial whether or not the treatment pack was opened or the allocated treatment started."
572,PMC3128457,S99,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,all site investigators and trial coordinating centre staff were masked to treatment allocation.
573,PMC3242163,S32,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients and randomisation,details of hps have been reported previously.1–3
574,PMC3242163,S33,"['4a', '5', '3a']","[0, 0, 0, 0, 0, 0, 1, 0, 1, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients and randomisation,"briefly, between july, 1994, and may, 1997, 20 536 men and women aged about 40–80 years, who were at increased risk of vascular events, were randomly allocated to receive 40 mg simvastatin daily or matching placebo."
575,PMC3242163,S34,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients and randomisation,"at the final follow-up (may–october, 2001), participants were encouraged to continue their allocated study treatment (unless it was contraindicated) until the study results were sent to them and their family doctors on nov 11, 2001."
576,PMC3242163,S35,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients and randomisation,"participants were advised to discuss with their doctors, in light of those results, whether non-trial statin treatment should be prescribed (and study treatment stopped)."
577,PMC3242163,S36,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients and randomisation,"to allow unbiased assessment of subsequent long-term effects, participants and their doctors were not made aware of their previously allocated study treatment unless there was a particular request to do so, and only 15% of participants were unblinded (18% simvastatin-allocated vs 13% placebo-allocated)."
578,PMC3242163,S38,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"during the in-trial treatment period, routine follow-up in study clinics was at 4, 8, and 12 months and then every 6 months."
579,PMC3242163,S39,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"information was sought about any suspected heart attacks, strokes, vascular procedures, cancers, or other serious adverse events."
580,PMC3242163,S40,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"participants unable or unwilling to attend were contacted by telephone, or follow-up was sought from their family doctors."
581,PMC3242163,S41,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"post-trial follow-up of serious adverse events was conducted by mailing questionnaires to all surviving participants in late november, 2001, and then annually until november, 2006, with a reminder mailed about 2 months later."
582,PMC3242163,S42,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,follow-up of participants who did not complete questionnaires was sought from their family doctors.
583,PMC3242163,S43,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"during both the in-trial and post-trial periods, information about the sites of registered cancers and certified causes of deaths was requested from uk national registries for all randomised patients."
584,PMC3242163,S44,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"further details were sought from the participants' family doctors (plus, if necessary, hospital records) about all reports that might relate to major vascular events or deaths."
585,PMC3242163,S45,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"in view of the high confirmation rate (>95%) in central adjudication of cancers reported during the in-trial period, further information was not routinely sought about non-fatal cancers reported during the post-trial period."
586,PMC3242163,S46,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"events were coded according to prespecified criteria1 by clinical staff in the coordinating centre, who were unaware of the study treatment allocation."
587,PMC3242163,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"during the in-trial period, compliance with study treatment was assessed at each follow-up by questioning the participant and reviewing their remaining calendar-packed tablets."
588,PMC3242163,S48,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"the effects of treatment allocation on cholesterol concentrations were assessed by assaying blood obtained at study clinics from a sample of about 5% of participants scheduled for follow-up at about the same time each year, and from all participants attending follow-up between august, 2000, and february, 2001.2"
589,PMC3242163,S49,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,"during the post-trial period, participants were asked each year about their current statin use, and post-trial lipid profile assays were sought from 1500 randomly selected surviving participants between may, 2004, and august, 2004 (ie, about 3 years after the scheduled treatment period)."
590,PMC3242163,S50,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures and follow-up,about 1100 blood samples were obtained by participants' family doctors and were mailed to a central laboratory for assay using previously validated methods.15
591,PMC3242163,S52,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Endpoints and statistical analysis,"the main comparisons entail log-rank analyses of the first post-randomisation occurrence of particular events during the in-trial period (defined as events occurring up to nov 11, 2001) and during the post-trial period (defined as events occurring from nov 11, 2001, until march 31, 2007) among all those originally allocated 40 mg simvastatin daily versus all those allocated matching placebo tablets (ie, intention-to-treat analyses)."
592,PMC3242163,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Endpoints and statistical analysis,"the results of these in-trial analyses differ slightly from previously published findings2,3 because of the inclusion of events taking place between the participants' final follow-up visit and nov 11, 2001 (mean extra follow-up of 3·5 months [sd 1·4])."
593,PMC3242163,S54,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Endpoints and statistical analysis,"the primary outcome for analyses of prolonged follow-up was prespecified to be the first post-randomisation major vascular event (defined as non-fatal myocardial infarction or coronary death, fatal or non-fatal stroke, coronary or non-coronary revascularisation)."
594,PMC3242163,S55,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Endpoints and statistical analysis,"secondary outcomes were: major vascular events during each year of follow-up and in various subcategories of patients; major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, and revascularisations separately; deaths from vascular and non-vascular causes separately; and cancers at all sites (excluding non-melanoma skin cancer)."
595,PMC3242163,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Endpoints and statistical analysis,"analyses are presented of other outcomes, some of which (eg, site-specific cancer, cerebral haemorrhage) were prespecified for the in-trial period whereas some were not (eg, cancer incidence each year)."
596,PMC3242163,S57,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Endpoints and statistical analysis,allowances for multiple comparisons and for the post-hoc nature of such analyses were made in their interpretation.
597,PMC3242163,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,"the trial was designed, conducted, analysed, and interpreted by the investigators, independently of all funding sources."
598,PMC3242163,S60,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,the writing committee had full access to the study data and had final responsibility for the decision to submit for publication.
599,PMC3266479,S37,"['4b', '3a']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,"we undertook a multicentre, pragmatic, double-blind, placebo-controlled, parallel-group, randomised trial at 46 uk intensive-care units between december, 2006, and march, 2010."
600,PMC3266479,S38,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,eligible participants were intubated and mechanically ventilated adults aged 16 years and older within 72 h of ards onset.
601,PMC3266479,S39,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,patients were identified and recruited by local investigators at each site.
602,PMC3266479,S40,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,"we defined ards in accordance with the american european consensus criteria:14 a pressure of arterial oxygen to fractional inspired oxygen concentration (pao2/fio2) ratio of 200 mm hg or less, bilateral pulmonary infiltrates consistent with oedema, and the absence of clinically evident left atrial hypertension."
603,PMC3266479,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,"exclusion criteria were pregnancy; current treatment with intravenous β-2 agonist or need for continuous, regular, aerolised β-2 agonists; current treatment with β-adrenergic antagonists; imminent withdrawal of medical treatment; chronic liver disease, defined as child-pugh grade c; and enrolment in another clinical trial of an investigational medicinal product within the previous 28 days."
604,PMC3266479,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,"sedated patients did not have capacity to give consent; therefore, consistent with requirements of the eu clinical trial directive,15 we obtained written informed consent from a personal or professional legal representative before randomisation."
605,PMC3266479,S43,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,all surviving patients were informed about the trial at the earliest opportunity after regaining competence and consent to continue in the trial was sought.
606,PMC3266479,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,the study protocol16 was approved for all centres by the oxfordshire research ethics committee a.
607,PMC3266479,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,site specific approval was obtained at each site.
608,PMC3266479,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,the trial was monitored for safety by an independent data monitoring and ethics committee.
609,PMC3266479,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"study drug packs were prepared by bilcare global clinical supplies (europe; powys, uk)."
610,PMC3266479,S49,"['9', '5']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 1]",Randomisation and masking,"the active and placebo drug components of the infusions were packaged identically into numbered treatment packs, each containing 5 ml of either salbutamol sulphate bp (1 mg/ml in a sterile isotonic solution, glaxosmithkline, middlesex, uk) or placebo (0·9% sterile sodium chloride)."
611,PMC3266479,S50,"['8b', '8a']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Randomisation and masking,we used a computer-generated randomisation sequence with a block size of eight.
612,PMC3266479,S51,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"patients were randomly assigned in a 1:1 ratio by a centralised 24 h telephone or web-based randomisation service (university of aberdeen, uk)."
613,PMC3266479,S52,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Randomisation and masking,"randomisation was minimised by centre, pao2/fio2 ratio (≤50, 51–99, or ≥100 mm hg), and age (<64, 65–84, ≥85 years)."
614,PMC3266479,S53,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"participants, care providers, and investigators were masked to group assignment."
615,PMC3266479,S55,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"we obtained acute physiology and chronic health evaluation ii (apache ii) scores from intensive care national audit and research centre (icnarc) for sites (n=36) that participate in the icnarc's case mix programme or, for non-participating sites (ten), we obtained data necessary for calculation of the scores."
616,PMC3266479,S56,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"we used the apache ii score to calculate the mortality risk, which we used for subgroup analysis."
617,PMC3266479,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"the most likely cause of ards was identified by the treating clinician and categorised as direct lung injury (smoke or toxin inhalation, aspiration of gastric content, near drowning, thoracic trauma, pneumonia, or other) or indirect lung injury (sepsis, cardiopulmonary bypass, pancreatitis, non-thoracic trauma, other)."
618,PMC3266479,S58,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"the protocol recommended use of a lung protective ventilation strategy on the basis of ideal bodyweight,17 fluid restriction,18 and appropriate high positive end-expiratory pressure.19"
619,PMC3266479,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,compliance with recommendations for protective ventilation were assessed at baseline only (tidal volumes per kg ideal bodyweight).
620,PMC3266479,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,all other treatments were delivered in accordance with local clinical practice.
621,PMC3266479,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"before the start of recruitment, the intensive-care unit nurse was trained to monitor side-effects of the treatment and to inform the research team as necessary."
622,PMC3266479,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,infusion syringes were prepared immediately before use by the nurse and contained two ampoules of the blinded solutions (salbutamol or placebo) diluted with 40 ml of saline in a 50 ml syringe.
623,PMC3266479,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,salbutamol and placebo were administered through a dedicated intravenous line at a rate of 0·075 ml/kg ideal bodyweight per h (equivalent to 15 μg salbutamol per kg ideal bodyweight per h).
624,PMC3266479,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"the patient was measured from heel to vertex with a soft tape measure, and the ideal bodyweight and infusion rate obtained from the conversion table.17"
625,PMC3266479,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"if any patient developed a tachycardia (heat rate >140 beats per min), new arrhythmia, or lactic acidosis, we adjusted the infusion rate according to a prespecified dose-adjustment schedule.15"
626,PMC3266479,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"infusion of the study drug was stopped at 7 days, or earlier if clinically indicated."
627,PMC3266479,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,"the primary outcome was 28-day mortality, defined as death up to the end of calendar day 28 after randomisation."
628,PMC3266479,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,"secondary outcomes were mortality in the intensive-care unit or hospital before first discharge; ventilator-free and organ failure-free days from randomisation to day 28; length of stay in intensive-care unit and hospital; and tachycardia, new arrhythmia, or other side-effects sufficient to stop treatment with trial drug."
629,PMC3266479,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,we defined ventilator-free days as the number of calendar days after patients started unassisted breathing until day 28 after randomisation for patients who survived at least 48 consecutive hours after start of unassisted breathing.20
630,PMC3266479,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,the number of ventilator-free days was zero for patients who died without start of unassisted breathing or before 48 consecutive hours of unassisted breathing.20
631,PMC3266479,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,"we defined organ failure-free days as the number of days in the first 28 days after randomisation that the patient received no cardiovascular, renal, liver, or neurological support as defined by the critical care minimum dataset.21"
632,PMC3266479,S73,['6b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0]",Study outcomes,"we did not plan to collect data for cause of death in the original trial protocol; however, after early termination of the trial because of the increased 28-day mortality in the salbutamol group, the data for the main cause of death were ascertained for all participants dying within 28 days of randomisation."
633,PMC3266479,S74,['6b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0]",Study outcomes,we requested causes of death as recorded on the death certificate for the disorder directly leading to death.
634,PMC3266479,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,"patients who remained alive and in critical care after randomisation were monitored daily until discharged to a ward, or until day 28."
635,PMC3266479,S77,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,we based the sample-size calculation on our balti trial13 and on 2005 data from the intensive care national audit and research centre.
636,PMC3266479,S78,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"the target sample size of 1334 gave 90% power at p<0·05 to detect a risk ratio (rr) of 0·8 for 28-day mortality between the salbutamol and placebo groups with a 3% loss of patients for the primary outcome, with the assumption that the 28-day mortality in the placebo group was 44%."
637,PMC3266479,S79,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Statistical analysis,"we planned interim analyses every 12 months, or more frequently if requested by the data monitoring and ethics committee."
638,PMC3266479,S80,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Statistical analysis,the committee used the haybittle-peto22 stopping guideline: a difference of three standard errors would be needed before considering recommending trial cessation for benefit at an interim analysis.
639,PMC3266479,S81,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,all analyses were based on intention-to-treat analyses.
640,PMC3266479,S82,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we compared the primary outcome and other dichotomous outcomes using rrs and 95% cis.
641,PMC3266479,S83,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we compared continuous outcomes with mean differences and their 95% cis.
642,PMC3266479,S84,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we analysed 28-day mortality with survival analysis, and by comparison of the two groups with hazard ratios and 95% cis and the kaplan–meier curve."
643,PMC3266479,S85,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,all reported p values are two-sided and were not adjusted for multiple comparisons.
644,PMC3266479,S86,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we used prespecified subgroup analyses to investigate the effects of age, severity of hypoxaemia at study entry, cause (direct vs indirect causes of ards), and the apache ii mortality risk, on the effect of salbutamol."
645,PMC3266479,S87,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all subgroup analyses used interaction tests; we either calculated the ratio of rrs between the subgroups, or used interaction terms in logistic regression models."
646,PMC3266479,S88,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we did a post-hoc analysis for the main causes of death as recorded on the death certificates of participants who died within 28 days of randomisation.
647,PMC3266479,S89,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"this trial is registered, isrctn38366450 and eudract number 2006-002647-86."
648,PMC3266479,S91,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,"the sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report."
649,PMC3266479,S92,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,"fgs, sg, gdp, and sel had full access to all the data in the study, and the corresponding author had final responsibility for the decision to submit for publication."
650,PMC3321505,S32,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,male and female patients aged 40–80 years expected to require daily nsaid therapy for at least 6 months for pain and/or inflammatory conditions were eligible.
651,PMC3321505,S33,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"exclusion criteria included history of erosive esophagitis; history of gi complications (bleeding, perforated ulcer, gastric outlet obstruction due to an ulcer); history of nsaid-associated asthma exacerbations, acute renal failure, interstitial nephritis, or hepatitis; history of gi malignancy; history of myocardial infarction, unstable cardiac arrhythmias, or stroke within 6 months of study entry; coronary artery bypass graft surgery within 14 days of study entry; uncontrolled congestive heart failure or hypertension at entry; acid-suppressive therapy or misoprostol within 14 days before study entry or investigational drug or nsaids (including aspirin >325 mg daily) within 30 days before study entry; ulcer or >5 erosions on screening upper gi tract endoscopy; or one of the following abnormalities on baseline laboratory testing: creatinine clearance <45 ml/min; aminotransferase >2.5 times upper limit of normal; fasting blood sugar >200 mg/dl; serum pregnancy test positive; serologic tests positive for human immunodeficiency virus, hepatitis b, or hepatitis c; or stool antigen for h. pylori positive."
652,PMC3321505,S35,"['8a', '9', '11b', '3a', '10']","[0, 1, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 1]",Study design,"patients were randomly assigned, using a computer-generated randomization schedule, from a central location utilizing an interactive voice response system with blinded medication kit number allocation in a 2:1 ratio to identical-appearing tablets of hzt-501 (800 mg ibuprofen and 26.6 mg famotidine) or ibuprofen (800 mg) thrice daily for 24 weeks."
653,PMC3321505,S36,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"patients, care providers, and all study personnel were blinded to the treatment."
654,PMC3321505,S37,"['3a', '8b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Study design,patients were stratified for two risk factors for ulcer development: concomitant use of low-dose aspirin (≤325 mg daily) and/or anticoagulant medication and history of gastric or duodenal ulcer.
655,PMC3321505,S38,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,"in addition to the screening upper endoscopy at baseline, patients had endoscopy at weeks 8, 16, and 24 (or earlier if premature study termination) of study therapy."
656,PMC3321505,S39,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"the following medications were proscribed during the study: medications that may reduce ulcers (e.g., misoprostol, proton-pump inhibitors, and non-study h2ras), non-study nsaids other than low-dose aspirin taken for cardiovascular prophylaxis."
657,PMC3321505,S40,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"in addition, antacids could not be taken for >3 days in any 2-week period; patients requiring further antacid therapy were to be discontinued from the trial."
658,PMC3321505,S41,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"the study medication was dispensed in an 8-week supply at 0, 8, and 16 weeks."
659,PMC3321505,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,compliance was determined by pill count of returned bottles of study medication.
660,PMC3321505,S43,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"serum chemistries, complete blood count, and prothrombin time were performed at screening, week 8, week 16, and the final study visit (week 24 or earlier if early termination)."
661,PMC3321505,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,urinalysis was done at baseline and final visit.
662,PMC3321505,S46,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",End points and analysis,"the primary end point for reduce-1 was gastric ulcers identified at endoscopy during the 24-week study period, with three secondary end points: upper gi ulcers (gastric and duodenal), duodenal ulcers, and gi complications (bleeding, ulcer perforation, and gastric outlet obstruction due to ulcer)."
663,PMC3321505,S47,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",End points and analysis,"the primary end point for reduce-2 was upper gi (gastric or duodenal) ulcers identified at endoscopy during the 24-week study period, with three secondary end points: gastric ulcers, duodenal ulcers, and gi complications."
664,PMC3321505,S48,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",End points and analysis,an endoscopic diagnosis of ulcer required unequivocal depth and diameter of ≥3 mm.
665,PMC3321505,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"the predefined primary population for analysis included all patients who were randomized, received a dose of study medication, and had at least one study-mandated follow-up endoscopy."
666,PMC3321505,S50,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",End points and analysis,a sample size for reduce-1 of 875 was calculated based on a 90% power to detect a difference of 6% vs. 14% in the incidence of gastric ulcers with a two-sided α of 0.05 and assuming a 15% drop-out rate.
667,PMC3321505,S51,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",End points and analysis,a sample size for reduce-2 of 600 was calculated based on a 90% power to detect a difference of 6% vs. 16% in the incidence of upper gi ulcers with a two-sided α of 0.05 and assuming a 15% drop-out rate.
668,PMC3321505,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",End points and analysis,"statistical comparisons were predefined to be done with a fixed testing sequence (hierarchical) in the following order of primary followed by secondary end points: reduce-1: gastric ulcers, upper gi ulcers, duodenal ulcers, gi complications; reduce-2: upper gi ulcers, gastric ulcers, duodenal ulcers, gi complications."
669,PMC3321505,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"with this approach, the first null hypothesis that is accepted (i.e., p≥0.05) will cause immediate acceptance of all subsequent null hypotheses in the sequence (subsequent comparisons will be considered not significantly different and no statistical comparison will be performed)."
670,PMC3321505,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,this approach also requires no α adjustment for multiple comparisons (14).
671,PMC3321505,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,the two different primary end points in the individual studies were chosen to address both the more clinically relevant end point of upper gi ulcers (gastric and/or duodenal) and the traditional us fda (food and drug administration) end point of gastric ulcers.
672,PMC3321505,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"in clinical practice, physicians and patients are concerned about preventing ulcers, whether they are gastric or duodenal, and many clinical trials use this primary end point."
673,PMC3321505,S57,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"however, the fda generally has approved antisecretory medications for prevention of gastric ulcers (e.g., lansoprazole and esomeprazole)."
674,PMC3321505,S58,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"these two trials were designed to be used for registration, and, in pretrial meetings, the fda agreed to the use of the different end points in the two trials."
675,PMC3321505,S59,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"comparison between treatment arms of the crude proportions of patients with ulcers at 24 weeks with a cochran–mantel–haenszel test stratified by the two randomization risk factor strata (use of low-dose aspirin and other anticoagulants, prior ulcer history) was specified as the primary statistical analysis at the time of sample size calculation and study initiation."
676,PMC3321505,S60,['6b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0]",End points and analysis,"before study termination and unblinding, the primary analysis was changed to a comparison between treatment arms of the life table estimates of the proportion of patients with ulcers at 24 weeks employing a modified χ2 using the sum of squares from the life table in the error term, with the comparison of crude proportions using the cochran–mantel–haenszel test maintained as a secondary analysis."
677,PMC3321505,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,numbers-needed-to-treat (nnts) and absolute risk reductions were calculated using crude proportions.
678,PMC3321505,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",End points and analysis,"a pooled analysis of the patients in reduce-1 and -2 was prespecified, with the primary end point being upper gi ulcers, and the secondary end points being gastric ulcers and duodenal ulcers."
679,PMC3321505,S63,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"the proportion of patients developing ulcers was also prespecified to be assessed in the following subgroups: use of low-dose aspirin and/or anticoagulants, prior ulcer history, age (≥65 vs. <65 years), gender, and race."
680,PMC3321505,S64,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"in addition, post hoc subgroup analysis included use of low-dose aspirin alone, and presence or absence of erosions at screening endoscopy."
681,PMC3321505,S65,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"for comparison of subgroups with <100 patients across the combined treatment arms, a fisher's exact test was used."
682,PMC3321505,S66,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"the independent variables prior ulcer history, gender, age, low-dose aspirin use, baseline erosions, and therapy also were included in a proportional hazards model to determine the effect on the dependent variable of development of upper gi ulcer."
683,PMC3321505,S67,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,treatment-by-subgroup interaction was also assessed among these subgroups in the model.
684,PMC3321505,S68,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"a post hoc fixed effect meta-analysis of the results of the two studies for end points of upper gi, gastric, and duodenal ulcers was also performed (review manager 5.1, cochrane collaboration, copenhagen, denmark)."
685,PMC3321505,S69,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,statistical comparison between the study groups in the population of all patients randomized was also prespecified for common adverse events (occurring in >5% of patients) with a cochran–mantel–haenszel test.
686,PMC3321505,S70,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,"in addition, we prespecified comparison of the proportion of patients who reported any symptom consistent with dyspepsia (e.g., dyspepsia, upper abdominal pain or discomfort, epigastric pain or discomfort, stomach pain or discomfort; with and without nausea)."
687,PMC3321505,S71,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",End points and analysis,all study patients provided written informed consent and the study was approved by institutional review boards for all participating centers.
688,PMC3348565,S100,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,for our intention-to-treat analysis we included all children randomly assigned to our study groups.
689,PMC3348565,S101,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,for our per-protocol analysis we included children who in both groups received all doses with an interval between the doses of 60 and 120 days and had not violated the randomisation codes.
690,PMC3348565,S102,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we analysed the repeat episodes accounting for clustering within individuals.
691,PMC3348565,S103,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we made initial comparisons of time-to-an-episode between the two groups with log-rank tests and kaplan–meier plots.
692,PMC3348565,S104,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we estimated the incidence rate ratio (rr) for the episodes of pneumonia with cox proportional hazard models.
693,PMC3348565,S105,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we assessed violation of the proportionality assumption with schoenfeld residuals.
694,PMC3348565,S106,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"this study is registered with clinicaltrials.gov, number nct00548379."
695,PMC3348565,S108,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,"the sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report."
696,PMC3348565,S109,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,the corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
697,PMC3348565,S49,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"between nov 4 and dec 4, 2008, we did a community based randomised placebo-controlled superiority trial in kabul, afghanistan, within the catchment area of the maiwand teaching hospital, which serves an inner-city population."
698,PMC3348565,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"follow up ended in may, 2009."
699,PMC3348565,S51,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,the children we enrolled into our study largely came from five of the 18 socioeconomically deprived inner-city districts.
700,PMC3348565,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"we identified households with young children with detailed maps and advice from staff of the agha khan trust for culture, a non-governmental organisation working in the region."
701,PMC3348565,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"furthermore, the study field-supervisors mapped the region independently to verify the accuracy of the maps of the agha khan trust for culture, and during recruitment they visited every house in the mapped region to identify families with young children."
702,PMC3348565,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,20 pairs of female fieldworkers visited every home starting from streets closest to the hospital and radiating out until we reached our required sample size.
703,PMC3348565,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,those homes where the carer or infant was absent were revisited again within 4 weeks of the recruitment period.
704,PMC3348565,S56,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,our inclusion criteria were infants aged 1–11 months and living in our study region.
705,PMC3348565,S57,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"our exclusion criteria were families expecting to move to another town within 18 months, diagnosis of rickets or treatment with vitamin d in the previous 3 months, and clinical diagnosis of kwashiorkor or marasmus."
706,PMC3348565,S58,"['5', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Participants,"the fieldworkers obtained written informed consent from the mother, father, or another senior family member before recruitment; allocated the unique identification number (sequentially); and gave the first dose of vitamin d3 or placebo."
707,PMC3348565,S59,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,children with vomiting were excluded temporarily and enrolled 2 weeks later after recovery.
708,PMC3348565,S60,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,thumbprint or signature consent was obtained from the child's parents (mother and father if in kabul or another family member responsible for the child) at home if the child met our study criteria and after either the parent read the dari consent form or it was explained to him or her by the fieldworker.
709,PMC3348565,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"our study was approved by the ethics and review board of the ministry of public health of afghanistan (reference 422328; issued may 12, 2007) and the ethics committee of the london school of hygiene and tropical medicine (application number 5117; issued may 29, 2008)."
710,PMC3348565,S63,"['8a', '8b', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Randomisation and masking,"an independent statistician (shabbar jaffar, london school of hygiene and tropical medicine, london, uk) randomised unique identification numbers individually in fixed blocks of 20 to the vitamin d3 or placebo group by use of a random number generator with the sas routine."
711,PMC3348565,S64,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Randomisation and masking,"by use of the randomisation list, a pharmacist in the department of pharmacy, aga khan university hospital, karachi prepared 100 000 iu (2·5 mg) of vitamin d3 (cholecalciferol) in olive oil (sinochem ningbo laboratory, china) or placebo (olive oil) in sealed 2 ml plastic syringes labelled with the unique identification numbers."
712,PMC3348565,S65,"['11a', '11b']","[0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"the vitamin d3 and the placebo were the same colour (pale yellow), taste, and quantity (0·5 ml) and therefore the study staff and the families did not know to which group the children were assigned."
713,PMC3348565,S66,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,fieldworkers allocated children to randomisation groups during recruitment and gave vitamin d or placebo.
714,PMC3348565,S68,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"we chose a quarterly supplementation regimen because in routine programme conditions a quarterly regimen is likely to have better adherence than a daily regimen,13,14 and has been shown to be effective at maintaining the serum vitamin d concentration within normal ranges for 2–3 months in a french high-risk infant population.16"
715,PMC3348565,S69,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,the syringes containing vitamin d or placebo were stored in conditions recommended by the manufacturer—a dry cool environment—between 2 and 24 weeks before administration.
716,PMC3348565,S70,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"we provided each child with an identification card, which included a photograph of the child, to enable easy access to outpatient and out-of-hours paediatric services at the study hospital."
717,PMC3348565,S71,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,we encouraged families to bring their children to the study hospital for any illness for which quality treatment was offered free of charge.
718,PMC3348565,S72,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"four experienced paediatricians and 30 female fieldworkers (medical students, nurses, midwives, or community health workers) were rigorously trained in our study protocols, the integrated management of childhood illnesses strategy, and the assessment of signs and symptoms required by our study."
719,PMC3348565,S73,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,the quality of clinical assessment in the clinics and during home visits was monitored weekly by study supervisors.
720,PMC3348565,S74,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"the fieldworkers followed up the children every 2 weeks until june, 2009, to obtain background information, assess illness (symptom history and examination of chest in-drawing, body temperature [thermoval classic hartmann digital thermometer], signs of dehydration by skin pinching, respiratory rate count over 1 min with a stopwatch), and to refer to the study hospital if needed."
721,PMC3348565,S75,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,respiratory rate and anthropomorphic data were collected twice and we used the mean values in our analysis.
722,PMC3348565,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,all children clinically diagnosed with pneumonia were offered free chest radiographs taken by radiographers trained by a who trainer.
723,PMC3348565,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"the masked radiographs were read by two independent paediatric radiologists (based at the acute respiratory infections unit of the pakistan institute of medical sciences), experienced in reading paediatric chest radiographs from who vaccine trials, with who proformas for standardised interpretation of paediatric chest radiographs for the diagnosis of pneumonia.17"
724,PMC3348565,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"in case of disagreement, radiographs were read by a third independent radiologist and most decisions were accepted."
725,PMC3348565,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"we ascertained causes of death through scrutiny of hospital notes, and verbal autopsy interviews with the who standard questionnaire and review of the interview data by two physicians independently."
726,PMC3348565,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"we defined clinical pneumonia as a history of cough plus increased respiratory rate for age, chest in-drawing, or any danger sign (ie, not drinking or breastfeeding, convulsion, vomiting, lethargic or unconscious, stridor in a calm child)."
727,PMC3348565,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,we defined severe pneumonia as cough plus chest in-drawing and very severe diseases as cough plus any danger signs.
728,PMC3348565,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,our primary endpoint was the first episode of pneumonia from the time of enrolment confirmed by chest radiograph (consolidation or infiltrates).
729,PMC3348565,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,we defined as a new episode of pneumonia an episode happening 15 days or longer after the first.
730,PMC3348565,S84,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,we judged an episode happening within 14 days to be continuation of the previous episode.
731,PMC3348565,S85,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,we collected venous blood samples from randomly selected blocks of children on the basis of the assumption that each block had an equal number of children from the vitamin d3 and placebo groups.
732,PMC3348565,S86,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,this was to ascertain calcifediol serum concentrations 1 week after giving the first dose in the placebo group (a baseline value for the whole population) as well as early concentrations after the first vitamin d supplementation in the intervention group (70 in placebo and 69 in intervention groups).
733,PMC3348565,S87,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,we also collected samples at other times (appendix) from a different set of randomly selected children to check fluctuations in serum concentrations.
734,PMC3348565,S88,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"we stored the serum samples at −20°c and analysed them at the end of our study with ids-isys multi-discipline automated chemiluminescent assay (immunodiagnostic systems ltd, tyne and wear, uk) at the manchester royal infirmary, manchester, uk (supra-regional vitamin d reference laboratories accredited to iso9001:2000 and iso13485:2003 and participating in the vitamin d quality assurance scheme)."
735,PMC3348565,S90,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"we assumed that the incidence of the first or the only episode of pneumonia (first episode) in our placebo group would be 0·0585 per child per year based on the report that the incidence of acute lower respiratory infections in developing countries was greater than 0·65 per child per year,18 that 12% of these episodes were pneumonia, and 75% were first episodes."
736,PMC3348565,S91,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"given that 73% of children had vitamin d deficiency in the study region in 2005,12 and that the incidence of pneumonia was ten-times higher in vitamin d deficient children than in children without a deficiency in case-control studies1,2 we postulated that there would be at least a 35% reduction in pneumonia incidence in the vitamin d compared with the placebo group."
737,PMC3348565,S92,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,thus a study with 80% power and 95% significance needed 22 079 child-months per group (total of 2454 children for 18 months follow-up).
738,PMC3348565,S93,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,assuming a 20% loss to follow-up and allowing for protocol violations we intended to recruit 3050 children for 18 months follow-up.
739,PMC3348565,S94,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,data were entered into a microsoft access database (version 2007) and data processing and analysis was done in stata (version 11.0).
740,PMC3348565,S95,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we compared baseline characteristics and the distribution of our prestated confounders for intervention and placebo groups.
741,PMC3348565,S96,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,to assess the potential problem of multicollinearity we used pearsons correlation coefficient or cramers v (for paired categorical variables).
742,PMC3348565,S97,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"if a child was not seen for more than 45 days, at the two weekly visits, or at the hospital, they were censored for that period of our study."
743,PMC3348565,S98,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,these children could re-enter the study when next seen.
744,PMC3348565,S99,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we calculated person-time at risk for each child up to the date a child reached our primary endpoint, was last seen at the end of our study, or when censored because they were lost to follow-up."
745,PMC3386495,S100,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Randomisation and masking,"the independent data monitoring committee met at least annually to review the unmasked data on major outcome events in the trial, on the background stroke-unit care received by trial patients (to ensure it was equal in both treatment groups), relevant external data (including updates of the cochrane systematic review and reports from large-scale registries of rt-pa use) in strict confidence throughout the course of the trial."
746,PMC3386495,S101,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Randomisation and masking,the committee judged these data never met the protocol-specified criteria to recommend modification of the protocol or halt recruitment to the study.
747,PMC3386495,S102,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,the statistical analysis plan was published14 before unmasking of the authors to the data.
748,PMC3386495,S103,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,all randomly assigned patients were included in the analysis.
749,PMC3386495,S104,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"masked analysis of the patients' baseline characteristics showed clear differences in key prognostic factors (age, stroke severity, degree of ischaemic change on baseline ct or mri) in patients randomly assigned at different times after stroke onset, which might complicate the estimation of the effect of treatment overall and in subgroups.11"
750,PMC3386495,S105,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"therefore, the primary analysis of the effect of treatment on the primary outcome was adjusted by logistic regression for linear effects for the following covariates: age; national institutes of health stroke scale (nihss) score; time from onset of stroke symptoms to randomisation; and presence (vs absence) of ischaemic change on the prerandomisation brain scan according to expert assessment."
751,PMC3386495,S106,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,an unadjusted analysis is also presented.
752,PMC3386495,S107,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"the trial did not meet its original target of 6000 patients, and so was no longer adequately powered to detect a 3% absolute difference in the primary outcome (with 80% power and α=0·05)."
753,PMC3386495,S108,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"the statistical-analysis-plan writing committee, which did not have access to the accumulating data, was therefore expanded to include an independent statistician (gordon murray, university of edinburgh, edinburgh, uk) to advise on the correct approach."
754,PMC3386495,S109,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,the writing group was persuaded by the recent empirical evidence that the ordinal method was both statistically more efficient (effectively reducing the sample size required in stroke trials29) and robust against substantial deviations from the proportional assumption.30
755,PMC3386495,S110,"['6b', '3b']","[0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0]",Randomisation and masking,"we therefore specified in the statistical analysis plan an ordinal logistic regression analysis, as a secondary outcome, in which the ohs as a dependent variable had 5 levels: levels 4, 5, and 6 were combined into a single level and levels 0, 1, 2, 3 were retained as distinct."
756,PMC3386495,S111,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"in this model the treatment odds ratios between one level and the next were assumed to be constant, so a single parameter summarises the shift in outcome distribution between treatment and control groups."
757,PMC3386495,S112,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"for patients known to be alive at 6 months, but with an unknown ohs, we used the level of function recorded on the 7-day form (ie, measured at 7 days or before discharge from hospital) to impute 6-month functional status.14"
758,PMC3386495,S113,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,we chose this simple form of imputation because it effectively classified 6-month outcomes in patients for whom both 7-day and 6-month data were known (data not shown).
759,PMC3386495,S114,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,analyses were done with sas (version 9.2).
760,PMC3386495,S116,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"the sponsors of the study had no role in design, data collection, data analysis, data interpretation, or writing of the report."
761,PMC3386495,S117,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,the corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
762,PMC3386495,S36,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"ist-3 was a pragmatic10 international, multicentre, randomised-controlled, open-treatment trial."
763,PMC3386495,S37,"['11a', '3a']","[0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,the initial pilot phase was double-blinded and placebo-controlled.
764,PMC3386495,S38,['3b'],"[0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"at the end of the pilot phase, since the main phase compared treatment with open control, several additional measures were introduced to minimise bias in the assessment of early and late outcomes.11"
765,PMC3386495,S39,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"we have published reports of the rationale for the trial,12 the protocol,13 an update on recruitment, amendments to the protocol and the baseline characteristics of the patients recruited,11 and the statistical analysis plan.14"
766,PMC3386495,S40,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,the eligibility criteria can be summarised in terms of the uncertainty principle.15–17
767,PMC3386495,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,inclusion and exclusion criteria are listed in detail in the protocol.13
768,PMC3386495,S42,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"briefly, patients were eligible according to the following criteria: they had symp-toms and signs of clinically definite acute stroke; the time of stroke onset was known; treatment could be started within 6 h of onset; and ct or mri had reliably excluded both intracranial haemorrhage and structural brain lesions, which could mimic stroke (eg, cerebral tumour)."
769,PMC3386495,S43,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"additionally, if the patient had a clear indication for intravenous thrombolysis with rt-pa, they were to be treated in accordance with local guidelines."
770,PMC3386495,S44,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"equally, if the patient had a clear contraindication to treatment they were not to be entered in the trial."
771,PMC3386495,S45,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"only if both the clinician and the patient (or a relevant proxy for the patient) felt that the treatment was promising but unproven, could the patient be included in the trial after appropriate informed consent from the patient or a valid proxy."
772,PMC3386495,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"the protocol was approved by the multi-centre research ethics committees, scotland (reference mrec/99/0/78), and by local ethical committees."
773,PMC3386495,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"this study is registered, isrctn25765518."
774,PMC3386495,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,table 1 baseline characteristics
775,PMC3386495,S50,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,clinicians entered baseline data via a telephone voice-activated or a secure web-based randomisation system.
776,PMC3386495,S51,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"after the system had recorded and checked the data, patients were allocated either immediate thrombolysis with 0·9 mg/kg of intravenous rt-pa to a maximum of 90 mg (10% bolus with the remainder over 1 h) or control treatment."
777,PMC3386495,S52,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,the system would not accept patients with blood pressure or glucose levels outside protocol-defined criteria (appendix pp 4–5) or other data inconsistencies.
778,PMC3386495,S53,"['10', '8b']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Study design and patients,"the system used a minimisation algorithm to achieve optimum balance for key prognostic factors (table 1), and from january, 2006, minimisation was additionally stratified by world region and then minimised on all the other key factors within regions."
779,PMC3386495,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"to be eligible to join the trial, participating hospitals had to have an organised system of stroke care."
780,PMC3386495,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"acute-care protocols were not specified by the trial, but had to include the components of effective stroke-unit care,19 including, soon after admission, intravenous access, monitoring of physiological variables, correction of any abnormalities, and where clinically appropriate, intravenous-fluid therapy."
781,PMC3386495,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"all patients in the trial were to be treated within that organised system of stroke care, irrespective of treatment allocation."
782,PMC3386495,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,patients allocated to the control group were to avoid treatment with rt-pa and received stroke care in the same clinical environment as those allocated to the rt-pa group.
783,PMC3386495,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,both treatment groups had blood pressure monitored closely over the first 24 h.
784,PMC3386495,S59,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"in the double-blinded phase, both groups were to avoid antiplatelet or anticoagulant therapy for 24 h."
785,PMC3386495,S60,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"in the open phase, patients allocated to the control group were to start aspirin immediately."
786,PMC3386495,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"blood pressure was managed in the same way in both treatment groups, according to local protocol."
787,PMC3386495,S62,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"additionally, all centres were asked for their pretrial experience of thrombolysis for treatment of stroke, and if the centre had, before joining the trial, a protocol for open-label use of rt-pa and had treated at least three people in the 12 months before joining the trial, the centre was classed as experienced."
788,PMC3386495,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and patients,all patients had a ct or mri brain scan before randomisation and a follow-up scan at 24–48 h.
789,PMC3386495,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and patients,a repeat brain scan was required if the patient deteriorated neurologically or intracranial haemorrhage was suspected for any reason.
790,PMC3386495,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and patients,"although ct scanning was preferred, mri was allowed."
791,PMC3386495,S66,"['6a', '11a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and patients,"all scans were sent to the trial centre in edinburgh for masked central rating of any signs of visible early ischaemia (presence and extent of hypo-attenuation, swelling, hyperattenuated artery), haemorrhage, and background brain changes (leukoaraiosis, atrophy, prior stroke lesions, non-stroke lesions) with validated rating methods.20–25"
792,PMC3386495,S67,"['11a', '6a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and patients,"images were assessed with all original identifiers stripped from the record, and then viewed via a secure web-based image viewing system by an international panel of expert radiologists."
793,PMC3386495,S68,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,all assessments were made masked to all patient details and treatment allocation.
794,PMC3386495,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and patients,"the primary outcome specified in version 1·93 of the protocol and in the published statistical analysis plan14 was the proportion of patients alive and independent as measured by the oxford handicap score (ohs),26 a commonly used variant of the modified rankin score.27"
795,PMC3386495,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and patients,"patients with an ohs of 0, 1, or 2 were classed as independent."
796,PMC3386495,S71,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,the statistical analysis plan specified an ordinal analysis of the ohs score at 6 months.
797,PMC3386495,S72,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,additional secondary outcomes were to be reported separately.
798,PMC3386495,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and patients,"events occurring within 7 days of stroke were recorded by the local trial clinician on the 7-day form: deaths subdivided by cause (swelling of the initial infarct, intracranial haemorrhage, other deaths from the initial stroke, recurrent ischaemic stroke, recurrent stroke of unknown type, any other cause); symptomatic intracranial haemorrhage; recurrent ischaemic stroke; recurrent stroke of unknown type; neurological deterioration attributed to swelling of the initial ischaemic stroke; neurological deterioration not attributable to swelling of the initial ischaemic stroke or haemorrhage; and major extracranial haemorrhage (operational definitions of each of these events are provided in the published protocol13 and statistical analysis plan14)."
799,PMC3386495,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and patients,other fatal and non-fatal non-cerebral events were also recorded and coded.
800,PMC3386495,S75,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,data on potential reports of any of these events were extracted from the trial database and presented to the adjudication committee who were masked to treatment allocation.
801,PMC3386495,S77,['8a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Randomisation and masking,"to avoid predictable alternation of treatment allocation, and thus potential loss of allocation concealment, patients were allocated with a probability of 0·80 to the treatment group that would minimise the difference between the groups on the key prognostic factors."
802,PMC3386495,S78,['8a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Randomisation and masking,additional details of the procedures used in the double-blinded phase of the study are reported elsewhere.11
803,PMC3386495,S79,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"the randomisation system informed local clinicians of the patients' unique trial identification number, and the weight-adjusted dose of drug or placebo in the double-blinded phase, or of the weight-adjusted drug dose among those allocated thrombolysis in the open phase, to be given as a 10% bolus with the remainder by an infusion over 1 h."
804,PMC3386495,S80,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"with the exception of the 276 patients treated in the double-blinded phase of the trial, treatment was given openly and neither the patient nor the treating clinicians were masked."
805,PMC3386495,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"hospital staff completed an early outcome form at 7 days, death, or hospital discharge, whichever occured first, recording details of events occurring in hospital within 7 days, details of background treatments given and functional status."
806,PMC3386495,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"6 months after randomisation, general practitioners (or hospital coordinators) were contacted by the ist-3 trial office staff to check that the patient was alive and inform them that they might be approached for follow-up."
807,PMC3386495,S83,"['11a', '6a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"if appropriate, the ist-3 trial office masked staff then mailed a postal questionnaire to patients to assess outcome."
808,PMC3386495,S84,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"non-responders were contacted by telephone, and follow-up data was obtained by telephone interview."
809,PMC3386495,S85,"['6a', '11a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"in italy and austria, all follow-ups were done as telephone interviews by a clinician, who was masked to treatment allocation and was highly experienced in outcome assessment."
810,PMC3386495,S86,"['6a', '11a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"in portugal, patients were followed up in clinic by clinicians not involved in the patients' initial treatment, again, masked to treatment allocation as far as possible."
811,PMC3386495,S87,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"to assess the durability of any treatment benefit beyond 6 months, patients recruited in the uk (and in other countries where appropriate funding had been obtained) were also followed up at 18 months."
812,PMC3386495,S88,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"all follow-up done by patient contact for these analyses ceased on march 31, 2012, but recording of deaths from national registries of deaths continues in uk, norway, and sweden."
813,PMC3386495,S90,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Randomisation and masking,"at the outset of the trial in 2000, we estimated that, among the type of patients likely to be recruited at the time, to detect both an absolute difference of 10% in the proportion of patients alive and independent at 6 months after treatment and to have sufficient power to permit reliable analyses of the prespecified subgroups, a sample of 6000 patients would be needed."
814,PMC3386495,S91,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Randomisation and masking,"a trial of that size could detect a clinically worthwhile net benefit of as little as 3% absolute difference in the primary outcome (80% power, α=0·05)."
815,PMC3386495,S92,['3b'],"[0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"however, it was clear by 2007 that obtaining a sample of 6000 was no longer feasible, and the steering committee agreed a revised recruitment target.11"
816,PMC3386495,S93,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Randomisation and masking,"the sample size, re-estimated in 2007 on the basis of event rates in both treatment groups combined, was 3100."
817,PMC3386495,S94,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Randomisation and masking,this sample size gave 80% power to detect an absolute difference of 4·7% in the primary outcome.11
818,PMC3386495,S95,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"we monitored the quality and integrity of the accumulating clinical data according to a protocol agreed with the study sponsors, which involved central statistical monitoring according to the principles described by buyse and colleagues,28 supplemented by onsite monitoring and detailed source data verification in a random sample of 10% of records in centres that had recruited more than 30 patients, or when patterns in the data at a centre seemed anomalous."
819,PMC3386495,S96,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"all ist-3 monitoring procedures were compliant with requirements of all study sponsors, the national ethics committees and regulatory agencies in the 12 participating countries, and they met all appropriate regulatory and good clinical practice requirements."
820,PMC3386495,S97,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"all baseline data, 7-day, and 6-month outcome data were subject to verification checks built into the randomisation and data management system."
821,PMC3386495,S98,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"we monitored all baseline and postrandomisation imaging, which provided additional cross-checks on recruited patients and centre performance."
822,PMC3386495,S99,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"an expert radiologist checked all scans, masked to clinical details and treatment allocation, immediately on receipt at the trial office, for evidence of adverse events and protocol deviations."
823,PMC3391717,S39,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"we did this phase 3 randomised, placebo-controlled trial at six dutch, one scottish, and one chilean centre."
824,PMC3391717,S40,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,the trial protocol has been published.11
825,PMC3391717,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,patients were eligible for inclusion if they were admitted to the neurological or neurosurgical units of one of the participating hospitals within 4 days of haemorrhage.
826,PMC3391717,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"investigators based the diagnosis of aneurysmal subarachnoid haemorrhage on the presence of extravasated blood in the basal cisterns by brain ct, or—if ct was negative—by xanthochromia of cerebrospinal fluid."
827,PMC3391717,S43,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"for patients with a normal ct scan and xanthochromia of cerebrospinal fluid, proof of an aneurysm was a prerequisite for inclusion."
828,PMC3391717,S44,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,we included patients with a perimesencephalic pattern of haemorrhage on ct only if they had an aneurysm of the posterior circulation.
829,PMC3391717,S45,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,"exclusion criteria were age younger than 18 years, renal failure (defined as serum creatinine concentration of more than 150 μmol/l), bodyweight less than 50 kg, or imminent death."
830,PMC3391717,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,the study complies with the declaration of helsinki and good clinical practice guidelines.
831,PMC3391717,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,we obtained ethics committee approval from every centre.
832,PMC3391717,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and patients,all patients provided written and oral informed consent.
833,PMC3391717,S50,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,the randomisation code was produced by the university medical center utrecht (the netherlands) pharmacy.
834,PMC3391717,S51,"['8a', '8b']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Randomisation and masking,"the pharmacy used computer-generated randomisation codes in blocks of four, and stratified by centre."
835,PMC3391717,S52,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Randomisation and masking,"the pharmacy produced identical, sequentially numbered, randomly assigned boxes of study medication, containing either magnesium sulphate or placebo."
836,PMC3391717,S53,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,local investigators assigned the participant to the box with the lowest study number.
837,PMC3391717,S54,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,the randomisation key was kept by the pharmacy of the university medical center utrecht.
838,PMC3391717,S55,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"patients, treating physicians, and investigators assessing outcomes and analysing data were masked to the allocation."
839,PMC3391717,S57,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"at admission to hospital, investigators recorded sex, age, and world federation of neurological surgeons subarachnoid haemorrhage grade12 for each patient."
840,PMC3391717,S58,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"a score of 1–3 was deemed a good clinical condition, and a score of 4–5 was deemed a poor clinical condition."
841,PMC3391717,S59,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"study medication consisted of vials containing 64 mmol magnesium sulphate or placebo (saline), produced by the pharmacy of the university medical center utrecht and distributed to the participating centres (except for the centre in chile, which produced its own study medication)."
842,PMC3391717,S60,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,an intravenous magnesium dosing regimen of 64 mmol per day after aneurysmal subarachnoid haemorrhage is safe and maintains serum magnesium concentrations at between 1·0 and 2·0 mmol/l.13
843,PMC3391717,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"furthermore, symptomatic hypermagnesaemia does not occur in patients with normal renal function.14"
844,PMC3391717,S62,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"therefore, participants received a fixed daily dose of 64 mmol magnesium sulphate reconstituted in 0·9% saline, or placebo, as soon as possible after providing consent."
845,PMC3391717,S63,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"investigators administered study medication continuously via intravenous infusion and continued for 20 days after haemorrhage onset, or until hospital discharge or death if it occurred sooner."
846,PMC3391717,S64,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,investigators checked renal function at least once every 2 days to prevent symptomatic hypermagnesaemia.
847,PMC3391717,S65,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,monitoring of magnesium concentration was not mandatory.
848,PMC3391717,S66,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"we discouraged, but permitted, investigators to treat hypomagnesaemia at admission with intravenous magnesium sulphate."
849,PMC3391717,S67,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"investigators treated patients according to local protocols, which included oral nimodipine 360 mg/day, bed rest until aneurysm occlusion, and early aneurysm occlusion, and aimed at achievement of normovolaemia."
850,PMC3391717,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"the primary outcome was dependence15 (defined as a modified rankin scale score of 4 or 5) or death, 3 months after haemorrhage."
851,PMC3391717,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"the research nurse and study coordinator collected outcome data centrally, and assessed the rankin score by semi-structured telephone interview in the patient's own language."
852,PMC3391717,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"the interview was translated into dutch and spanish with the standard procedure16,17 for forward–backward translation."
853,PMC3391717,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,secondary outcome measures were no symptoms (modified rankin scale score of 0) 3 months after haemorrhage and the difference between the distribution of all scores on the modified rankin scale.
854,PMC3391717,S73,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"in our pilot study, 35% of patients in the untreated group had a poor outcome compared with 27% in the intervention group (rr 0·77).10"
855,PMC3391717,S74,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,on the basis of these data we estimated that 1082 patients would be needed to confirm this effect with an α of 5% and 80% power.
856,PMC3391717,S75,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,to allow for reliable detection of a slightly smaller effect (risk ratio 0·78) we decided to enrol 1200 patients.
857,PMC3391717,S76,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,a research nurse entered all baseline and outcome data in the study database.
858,PMC3391717,S77,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the study coordinator analysed the data.
859,PMC3391717,S78,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the data were checked and results discussed by the executive committee.
860,PMC3391717,S79,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Statistical analysis,"the data monitoring committee did two interim analyses during the study, after 350 and 750 patients had completed 3-month follow-up, with reference to a pre-defined stopping rule, and recommended continuation of the trial on both occasions."
861,PMC3391717,S80,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we analysed the results according to intention to treat by comparing poor outcome at 3 months in each group with a risk ratio and 95% ci.
862,PMC3391717,S81,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we did planned sensitivity analyses by assigning patients lost to follow-up to either a good outcome or a poor outcome irrespective of treatment group, and assigning patients with unknown randomisation codes to either the magnesium group or the placebo group."
863,PMC3391717,S82,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"planned subgroup analyses were done according to age, sex, clinical condition at admission, method of treatment of aneurysm, and whether the centre treated hypomagnesaemia with intravenous magnesium supplementation."
864,PMC3391717,S83,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we compared the distributions of the modified rankin scale scores with the non-parametric mann-whitney u test.
865,PMC3391717,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we updated our previous cochrane meta-analysis5 with results of mash 2 and eligible randomised trials that had been published since the start of mash 2 and the last update of the cochrane review.18–20
866,PMC3391717,S85,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we used cochrane review manager (version 5.1) software for the meta-analysis and spss (version 15.0) for all other analyses.
867,PMC3391717,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,this study is registered with controlled-trials.com (isrctn 68742385) and the eu clinical trials register (eudract 2006-003523-36).
868,PMC3391717,S88,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,"the sponsor had no role in study design, data collection, data analysis, data interpretation, or writing of the report."
869,PMC3391717,S89,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,the corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.
870,PMC3489506,S33,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and oversight,"this randomised, parallel group, double masked, multicentre, placebo controlled, phase iii trial was undertaken at 19 sites in england and wales."
871,PMC3489506,S34,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and oversight,the trial was independently overseen by an independent data safety monitoring committee and a trial steering committee.
872,PMC3489506,S36,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population,"children were eligible to participate if they were aged between 3 years and 15 years 8 months at registration visit, had a neurodevelopmental disorder scoring 1.5 sd or more below the mean on the adaptive behaviour assessment system (abas),11 and had a sleep disorder reported by parents for at least the past five months characterised as failing to fall asleep within one hour of “lights off” in three nights out of five or achieving less than six hours of continuous sleep in three nights out of five, or both."
873,PMC3489506,S37,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population,children were required to be free from drugs that could cause sleepiness and no have taken no melatonin within the preceding five months.
874,PMC3489506,S38,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population,"at registration, parents/carers were provided with a booklet of advice on previously trialled and standardised sleep behaviour treatment.12"
875,PMC3489506,S39,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population,this was used as a run in to ensure that children who progressed to the randomisation phase did not include those whose sleep disorder could have been amenable to treatment with non-pharmacological intervention.
876,PMC3489506,S40,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population,"sleep was monitored during the registration period by using sleep diaries completed by parents, and children were randomised if they continued to fulfil the eligibility criteria with the sleep disorder criteria evident from these sleep diaries."
877,PMC3489506,S42,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study intervention,the child’s age appropriate bedtime was established at the start of the registration period and the trial drug was administered 45 minutes before this time either orally or through a feeding tube if required.
878,PMC3489506,S43,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study intervention,"if the child was tube fed, the capsule was opened and the study treatment suspended in an appropriate medium.12"
879,PMC3489506,S44,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study intervention,"at randomisation, each child was given 0.5 mg."
880,PMC3489506,S45,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study intervention,"at each of four weekly intervals, the child’s sleep pattern, as recorded on the sleep diary, was reviewed and the dose was increased to the next dose increment on the basis that the child fulfilled the sleep disorder eligibility criteria, had received at least five of the possible seven doses in the preceding week, and had not experienced any serious adverse events."
881,PMC3489506,S46,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study intervention,"there was a maximum of three dose increments from 0.5 mg, 2 mg, 6 mg, and a maximum of 12 mg."
882,PMC3489506,S47,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study intervention,step down in dose was possible if adverse effects were experienced at a higher dose.
883,PMC3489506,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study intervention,"participants were followed up for 12 weeks from randomisation with a combination of home visits, telephone calls, and clinic attendance."
884,PMC3489506,S50,"['8a', '8b', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Randomisation,"the trial statistician generated randomisation lists in stata (release 9, college station, tx) in a 1:1 ratio using block randomisation with random variable block lengths of two and four stratified by centre."
885,PMC3489506,S51,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,the statistician had no further access until determination of the analysis population.
886,PMC3489506,S52,['11b'],"[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,the placebo capsules and contents were identical in internal and external appearance.
887,PMC3489506,S53,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Randomisation,treatment packs were numbered sequentially and dispensed by the pharmacy of each site.
888,PMC3489506,S54,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Randomisation,treatment packs held enough drugs for the 12 week period and allowed for potential dose escalation.
889,PMC3489506,S55,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,all trial staff and participants were blind to treatment allocation throughout the trial.
890,PMC3489506,S57,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Measuring sleep,"the trial design included both subjective (diary) and objective (actigraphy) measures of sleep, as recommended by sadeh.13"
891,PMC3489506,S58,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Measuring sleep,"there are benefits with each approach and reasons why the results might not be concordant4 7; for example, sleep diaries would not detect periods when the child was awake but not disturbing the household (a particular concern for determining sleep onset latency), and actigraphy could interpret restless sleep as being awake."
892,PMC3489506,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Measuring sleep,"between registration and study completion, parents were asked to complete weekly sleep diaries."
893,PMC3489506,S60,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Measuring sleep,"the actigraph (micromini-motionlogger, ambulatory monitoring, new york), an accelerometer, is worn on the wrist and movement is monitored continuously and stored within the unit."
894,PMC3489506,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Measuring sleep,subsequent analysis of frequency and pattern of movement by means of validated algorithms permits detection of basic sleep-wake patterns.13
895,PMC3489506,S62,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Measuring sleep,children wore the actigraph continuously between registration and randomisation and the 12th week after randomisation.
896,PMC3489506,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,"the primary outcome was total sleep time, measured by diaries completed by parents."
897,PMC3489506,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,each night the minutes between the times that the child went to sleep and woke up the next morning were calculated minus any night time awakenings.
898,PMC3489506,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,a minimum of five out of seven nights’ data at baseline (the week before randomisation) and during the final week were required and the weekly average calculated at each time point.
899,PMC3489506,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,secondary sleep outcomes included total sleep time measured by actigraphy; sleep onset latency measured by diaries and actigraphy; and sleep efficiency (the proportion of time spent in bed asleep) measured by actigraphy.
900,PMC3489506,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,"sleep onset latency measured the time taken for a child to go to sleep from “snuggle down” time recorded on the sleep diary for both sleep diary and actigraphy measures, with onset of sleep determined by the respective methods."
901,PMC3489506,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,four questionnaires were completed at baseline and at the final visit: the composite sleep disturbance index (csdi; based on allocating scores according to the frequency and duration of sleep problems reported by parents in questionnaires)14 15 16; the aberrant behaviour checklist (abc) to assess behavioural problems17 18; the family impact module of the paediatric quality of life inventory (pedsql) to assess the quality of life of the care giver19; and the epworth sleepiness scale (ess) to assess the daytime sleepiness of the care giver.20
902,PMC3489506,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,we used a seven point likert scale to assess parental perception of child’s sleep quality.
903,PMC3489506,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,we measured salivary melatonin concentrations for each participant to calculate dim light melatonin onset (dlmo).
904,PMC3489506,S72,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study outcomes,melatonin is a hormone produced by the pineal gland in a circadian rhythm influenced by light levels.
905,PMC3489506,S73,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study outcomes,"concentrations are usually low during the day, but as evening approaches they start to rise sharply peaking at around midnight."
906,PMC3489506,S74,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study outcomes,the beginning of this rise is what is known as the dim light melatonin onset time.
907,PMC3489506,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,salivary samples were collected at two time points on the night before the randomisation clinic visit and at the beginning of the 11th week with two nights of trial treatment omitted.
908,PMC3489506,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,saliva samples were collected hourly from 5 pm until the child’s usual bedtime.
909,PMC3489506,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study outcomes,a minimum of 2 ml of saliva was obtained by asking the child to spit into a tube or by placing a saliva sponge in the buccal cavity of the child’s mouth.
910,PMC3489506,S78,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study outcomes,saliva samples were also taken for dna analysis to identify genetic polymorphisms associated with the sleep outcomes.
911,PMC3489506,S79,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study outcomes,dna analyses are ongoing.
912,PMC3489506,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety assessments,a paediatrician physically examined the children at the screening and final visits.
913,PMC3489506,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety assessments,"the frequency and severity of spontaneously reported adverse events were recorded weekly along with prompted reports of adverse events of interest (treatment emergent signs and symptoms) covering somnolence, increased excitability, mood swings, rash, hypothermia, and cough."
914,PMC3489506,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety assessments,weekly seizure diaries recording the type and number of seizures were completed for those children with a pre-existing diagnosis of epilepsy.
915,PMC3489506,S84,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety assessments,the investigator’s brochure was referred to in the assessment of causality and expectedness.
916,PMC3489506,S86,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Exploratory analyses,"interactions between treatment and autism, the type of sleep disorder (categorised as delayed sleep onset, poor sleep maintenance, or both), baseline measurements, and child’s age and weight were considered for the primary outcome and sleep onset latency as post hoc analyses."
917,PMC3489506,S87,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Exploratory analyses,additional analyses assessed whether there was a change in morning wake up time and number and duration of night awakenings to determine whether the observed increase in total sleep time was explained by reduced sleep onset latency.
918,PMC3489506,S89,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical considerations,"we used the “intention to treat” principle throughout and undertook analyses with sas (version 9.1.3, cary, nc)."
919,PMC3489506,S90,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical considerations,results are presented with 95% confidence intervals.
920,PMC3489506,S91,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical considerations,"continuous outcomes are presented with means and standard deviations at baseline, at study completion (week 12), and for the change from baseline for each group."
921,PMC3489506,S92,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical considerations,"we used analysis of covariance to adjust results for the dependent variables (total sleep time, sleep onset latency) measured at baseline and in exploratory analyses for treatment covariate interactions."
922,PMC3489506,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical considerations,the trial was originally designed with two primary outcomes: total sleep time according to the sleep diary and sleep onset latency measured with actigraphy.
923,PMC3489506,S94,['6b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0]",Statistical considerations,during trial recruitment we observed high rates of missing data (66%) for actigraphy so we re-designated sleep onset latency as a secondary outcome and removed the bonferroni multiplicity adjustment21 in a protocol amendment.
924,PMC3489506,S95,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical considerations,the process adopted in protecting trial validity was that suggested by evans.22
925,PMC3489506,S96,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical considerations,total sleep time was powered at 80% with a 5% significance level to detect a change from baseline of one hour between the melatonin and placebo group with a common standard deviation of 1.7.23 24
926,PMC3489506,S97,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical considerations,"allowing for 20% missing data based on observed rates at the time of the amendment, we calculated we needed 57 participants in each group."
927,PMC3489506,S98,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical considerations,"we reassessed the estimate of the common standard deviation used in the sample size calculation after the first 20 participants as 1.2 (95% confidence interval 0.8 to 1.7), and the independent data safety monitoring committee recommended the trial continue without revision of the sample size calculation for the estimated standard deviation used."
928,PMC3502035,S36,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,the australian universal health insurance scheme (medicare) provides citizens with free access to public hospitals and reimbursed access (70% of services with no co-payment) to a widespread network of primary care or general practice clinics.
929,PMC3502035,S37,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"a parallel system, the pharmaceutical benefits scheme, provides subsidised drug treatment to all australians, with capped payments for those with a chronic illness; most prescriptions for drugs being generated by general practitioners managing people with chronic conditions such as hypertension."
930,PMC3502035,S39,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,study participants were recruited by 260 general practitioners from 119 general practices distributed throughout every state and territory of australia except the sparsely populated northern territory.
931,PMC3502035,S40,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"people routinely managed by these doctors were potentially eligible to participate if they were aged 18 or more, had a diagnosis of hypertension requiring active drug treatment according to guidelines, and consented to participate."
932,PMC3502035,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"we excluded people who had a mean initial systolic blood pressure of 180 mm hg or more while sitting, were prescribed three or more antihypertensives; had moderate to severe renal disease (clinical diagnosis or estimated glomerular filtration rate <60 ml/min/1.73m2), or had contraindications to angiotensin receptor blockers, calcium channel blockers, or thiazide diuretics."
933,PMC3502035,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"recruitment took place from july 2009 to december 2010, with follow-up completed in july 2011."
934,PMC3502035,S44,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"this was an open label, two arm, randomised trial comparing an intensive blood pressure management strategy with usual care (control).13"
935,PMC3502035,S45,"['8a', '8b']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Study design,"randomisation was by computer generated, group assignment stratified according to nominated blood pressure target (three strata) and block randomisation (units of 12) per general practitioner."
936,PMC3502035,S46,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,an independent data management team at baker idi coordinated a standardised protocol for randomising participants over the telephone.
937,PMC3502035,S47,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,participants were assigned to the groups using a prespecified ratio of 1:2 for usual care versus intervention (with a further ratio of 1:2 within the intervention arm to assign participants to a monotherapy strategy and to two possible combined treatment strategies).
938,PMC3502035,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,quality control of the sites and general practitioners was achieved by visits before randomisation and at study end.
939,PMC3502035,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"the study was independently monitored by routine visits, and case report forms were verified against clinical records for 20% of patients."
940,PMC3502035,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,we used standardised operating procedures for data queries and management.
941,PMC3502035,S51,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,all queries were resolved by the time the study dataset was locked and no further changes were permitted.
942,PMC3502035,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,figure 1 provides a graphical representation of the study timelines.
943,PMC3502035,S53,"['3a', '5']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,fig 1 summary of study timelines
944,PMC3502035,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study entry,"eligible participants underwent baseline assessment, including determination of absolute cardiovascular risk.5"
945,PMC3502035,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study entry,"on the basis of this assessment, we identified target risk factor measures (including blood pressure, lipid levels, exercise levels, smoking status, and body mass index) for each participant according to national guidelines.6"
946,PMC3502035,S57,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study entry,a computer program developed by baker idi enabled clinical profiling in all participants and subsequent management in intervention patients (see appendix i in the supplementary file).
947,PMC3502035,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study entry,"eligible participants began a standard 28 day run-in period of treatment with open label, oral valsartan 80 mg daily, with a mandatory blood pressure check 14 days after the start of treatment to determine the need for immediate (rescue) randomisation if systolic blood pressure was ≥180 mm hg or clinically indicated."
948,PMC3502035,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study entry,we then randomised into the study those who did not achieve their prespecified blood pressure target within this run-in period or were not specifically withdrawn or lost to follow-up (blinded allocation).
949,PMC3502035,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Blood pressure measurement,throughout the study we used a standardised protocol based on national guidelines to record blood pressure measurements.6
950,PMC3502035,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Blood pressure measurement,"after participants had rested for at least five minutes and while they were seated we obtained three blood pressure measurements separated by one minute intervals using an appropriate sized cuff and a calibrated, semiautomated oscillometric device approved by the therapeutic goods administration of australia."
951,PMC3502035,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Blood pressure measurement,we defined aberrant measurements as those where the lowest reading was 10 mm hg or more for systolic blood pressure or 5 mm hg or more for diastolic blood pressure below the highest of the three seated readings.
952,PMC3502035,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Blood pressure measurement,"if this occurred, the participant was rested for three minutes and the procedure repeated."
953,PMC3502035,S65,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Blood pressure measurement,"given the size and nature of the study, it was impractical to obtain independent, blinded blood pressure levels."
954,PMC3502035,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Blood pressure measurement,"nominated study staff at each site (general practitioner or practice nurse) verified the blood pressure measurements by an independent audit of the clinical details in the case records, outputs from the blood pressure monitor, and the computer decision tool."
955,PMC3502035,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Usual care,"for those assigned to usual care, we asked general practitioners to follow their usual pattern of clinic visits and treatment strategies (no restriction on prescribed drugs) to achieve the individualised blood pressure target and other prevention targets identified during the run-in phase; the only mandatory study visits were at weeks 6 (a typically brief 10-15 minute consultation) and 26 (final comprehensive evaluation)."
956,PMC3502035,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Usual care,we explicitly acknowledged that this was an enhanced form of usual care given that the participants had already been subject to clinical profiling and had an identified blood pressure target and their doctors potentially had knowledge of the intervention (with the inherent problem of contamination).
957,PMC3502035,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study intervention,"those allocated to the intervention arm followed an intensive stepped programme of management, with mandatory visits to their doctor at weeks 6, 10, 14, and 18 after randomisation to review their blood pressure and to adjust their treatment if needed according to prespecified algorithms (see appendix ii in the supplementary file)."
958,PMC3502035,S72,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study intervention,"typically, these consultations lasted 10-15 minutes (about 60 minutes in total) in addition to the time taken for clinical profiling at baseline."
959,PMC3502035,S73,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study intervention,"reflecting contemporary treatment options for the management of hypertension, different drug pathways were mandated (initial monotherapy with valsartan 160 mg or combined with hydrochlorothiazide or amlodipine, as single combined pills)."
960,PMC3502035,S74,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study intervention,scheduling of visits and up-titration of drug treatment was guided by the same computer program developed by baker idi to facilitate the initial risk profiling and management.
961,PMC3502035,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study intervention,a final clinic visit for clinical re-evaluation was scheduled at 26 weeks.
962,PMC3502035,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,the primary endpoint was the percentage of participants who achieved their individualised blood pressure target according to national guidelines6 during 26 weeks of follow-up (using last recorded blood pressure for intention to treat analyses).
963,PMC3502035,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,"these stringent blood pressure targets, which have been rarely examined for feasibility in a controlled trial, are ≤125/75 mm hg if a patient has proteinuria, ≤130/80 mm hg if end organ damage is present (including any form of cardiovascular disease, diabetes, or microalbuminuria), and the classic target of ≤140/90 mm hg for those without evidence of the other two criteria."
964,PMC3502035,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,key secondary endpoints included change in mean sitting systolic and diastolic blood pressure and absolute risk for cardiovascular disease within five years based on the framingham risk score5 (where applicable).
965,PMC3502035,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,"secondary endpoints also included the type and rate of adverse events potentially attributable to antihypertensive treatment, and serious adverse events including all cause mortality and fatal and non-fatal cardiovascular events—for example, acute myocardial infarction, stroke, and heart failure."
966,PMC3502035,S81,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study endpoints,"several other secondary endpoints will be the subject of future or expanded reports, including changes in quality of life, depression, self care behaviours, and evidence of end organ damage (including electrocardiographic evidence of left ventricular hypertrophy and newly detected proteinuria)."
967,PMC3502035,S83,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study power,we largely met the study targets for overall recruitment and number of participants entering the run-in phase.
968,PMC3502035,S84,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Study power,"based on the combination of a strong potential for interventional contamination, balanced against the need to establish clinically significant differences between the two groups, the study was initially powered to detect a minimum absolute difference of 7% between the groups for the primary endpoint.13"
969,PMC3502035,S85,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Study power,"as proportionately more patients achieved blood pressure control during the study run-in and thus the number of randomised participants was reduced, we recalculated that a total randomised cohort of more than 1500 participants would still provide sufficient study power to detect a minimum 8% difference between groups with more than 85% study power (two sided α level of 0.05 and adjusting for 2:1 randomisation for study intervention versus usual care).13"
970,PMC3502035,S87,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the study statistician (on behalf of the clinical safety and efficacy committee) independently analysed the data according to a prospectively designed statistical analysis plan.
971,PMC3502035,S88,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"if blood pressure values were missing at 26 weeks, we carried forward the last recorded blood pressure measurement after randomisation for primary endpoint analysis."
972,PMC3502035,S89,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,baseline and outcome data were analysed using spss for windows version 19.0.
973,PMC3502035,S90,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,continuous data are presented as means (standard deviations) or medians (interquartile ranges).
974,PMC3502035,S91,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,categorical data are presented as percentages.
975,PMC3502035,S92,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"we carried out efficacy analyses on an intention to treat population, consisting of all participants randomised to the intervention arm or to the usual care arm and who had at least one recorded blood pressure measurement after randomisation."
976,PMC3502035,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,analyses were based on the treatment group to which the participant was randomised.
977,PMC3502035,S94,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,we compared the primary endpoint measure (blood pressure control at week 26) between the study groups using a log binomial generalised linear model with stratification status at randomisation as a covariate.
978,PMC3502035,S95,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"stratification status was fit as a categorical variable with the three blood pressure target groups (≤125/75 mm hg, ≤130/80 mm hg, and ≤140/90 mm hg) based on the participant’s clinical profile."
979,PMC3502035,S96,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"change in systolic and diastolic blood pressure from baseline to 26 weeks were each analysed by analysis of covariance, with treatment group and stratification status as factors and mean baseline blood pressure as a covariate."
980,PMC3502035,S97,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,we also describe the proportion and rate of adverse events (per participant).
981,PMC3551223,S157,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,web appendix
982,PMC3551223,S41,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"this report covers the planned analysis of the first 24 weeks (including the primary endpoint) of an on-going 2-year double-blind placebo controlled parallel-group clinical trial (nct00810199, eudract no 2008-001847-20)."
983,PMC3551223,S42,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"the treatment allocation of individual patients remained blinded for patients, site personnel and the data analysis/interpretation team, except for the separate subgroup technically preparing the data."
984,PMC3551223,S43,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the study was approved by the appropriate institutional review boards/ethics committees with written informed consent obtained from each patient before study participation.
985,PMC3551223,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"the study was conducted in full accordance with international conference on harmonisation/good clinical practice and the principles, laws and regulations of the countries in which the research was conducted."
986,PMC3551223,S46,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"eligible patients had confirmed ra according to the 1987 american college of rheumatology (acr) criteria with active disease defined as disease activity score based on 28 joints–erythrocyte sedimentation rate (das28–esr) greater than 4.4 at baseline and 4.0 or more at screening, and had been receiving methotrexate for at least 12 weeks, with a stable dose of at least 15 mg/week for 6 weeks or longer before starting study treatment."
987,PMC3551223,S47,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"for inclusion, patients were also required to have bone damage with radiographic evidence of at least one joint with definite erosion attributable to ra as determined by a central reader."
988,PMC3551223,S48,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"major exclusion criteria included severe comorbidities, any previous use of biological agents as well as any conventional disease-modifying antirheumatic drug treatment other than methotrexate during the month (3 months for leflunomide) preceding the baseline visit (see supplementary data, available online only, for full inclusion and exclusion criteria)."
989,PMC3551223,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study treatment,"patients were randomly assigned either to the add-on or the switch strategy group (see supplementary data, available online only, for study design schematic)."
990,PMC3551223,S51,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Study treatment,randomisation was stratified by study site and baseline das28–esr (≤ or >5.5) using a minimisation algorithm.
991,PMC3551223,S52,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatment,all patients received open-label tocilizumab 8 mg/kg intravenously every 4 weeks.
992,PMC3551223,S53,"['11b', '5']","[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatment,"treatment with methotrexate/placebo was double-blind: all patients received identical capsules of either placebo (switch strategy arm) or methotrexate 2.5 mg (add-on strategy arm), with the number of capsules at study entry being consistent with prestudy dosage."
993,PMC3551223,S54,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatment,"tocilizumab and/or disease-modifying antirheumatic drug treatment was reduced or temporarily interrupted in patients with alanine aminotransferase or aspartate transaminase values greater than one to three times the upper limit of normal (uln), and was discontinued for persistent increases greater than three times uln."
994,PMC3551223,S56,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Concomitant RA treatments,oral corticosteroids (≤10 mg/day prednisone or equivalent) and non-steroidal anti-inflammatory drugs were permitted as long as doses had been stable for at least 25 of 28 days before the start of study treatment.
995,PMC3551223,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Concomitant RA treatments,"alterations in the non-steroidal anti-inflammatory drug dose were not recommended during the study, particularly during the first 24 weeks."
996,PMC3551223,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Concomitant RA treatments,the corticosteroid dose could not be changed during the first 24 weeks of the study.
997,PMC3551223,S60,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,data collected at baseline included demographics and disease characteristics such as ra disease duration.
998,PMC3551223,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,"at baseline and every 4 weeks thereafter the following parameters were assessed: tender joint count, swollen joint count, health assessment questionnaire–disability index (haq–di), patient's global assessment, physician's global assessment, c-reactive protein (crp), esr."
999,PMC3551223,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,"quality of life was assessed at baseline and at weeks 4, 8, 12 and 24 using the rheumatoid arthritis quality of life questionnaire (raqol)."
1000,PMC3551223,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,"at each visit, patients were monitored for adverse events, vital signs and laboratory tests (eg, blood counts, transaminases, cholesterol)."
1001,PMC3551223,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,radiographs of the hands/wrists and feet were obtained at baseline and week 24.
1002,PMC3551223,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,"each radiograph was assessed applying the genant-modified sharp scoring system (gss) by two independent readers (perceptive informatics medical imaging services, berlin, germany) who were blinded to treatment assignment, chronological order of radiographs and patient's clinical status."
1003,PMC3551223,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,"the smallest detectable change (sdc) for gss was computed based on the observed sd of difference between the x-ray readers,14 whereas three readers in total participated in the campaign."
1004,PMC3551223,S67,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,the sdc is the smallest change that can be attributed to something more than observed variability of reader differences.
1005,PMC3551223,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the clinical superiority of the tocilizumab plus methotrexate combination treatment in the phase ii charisma study13 had an important influence on the statistical parts of the design.
1006,PMC3551223,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"to assess the working hypothesis that the add-on strategy (ie, initiation of tocilizumab plus continuation of methotrexate) would be superior to the switch strategy (ie, initiation of tocilizumab and discontinuation of methotrexate), the primary outcome measure of the study was defined as the percentage of patients in remission according to das28–esr (das28 <2.6) at week 24."
1007,PMC3551223,S71,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,a two-sided statistical test of no difference between the two treatment arms at the 5% significance level was used.
1008,PMC3551223,S72,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"specifically for the primary endpoint, as well as for similar endpoints, a logistic regression model was employed including the stratification factors used at randomisation (site and baseline das28 ≤ or >5.5) with a supportive cochran–mantel–haenszel test stratified for the same parameters."
1009,PMC3551223,S73,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,analysis of covariance models were used to compare continuous outcome measures.
1010,PMC3551223,S74,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"efficacy analyses were conducted in the intention-to-treat population (all randomly assigned and treated patients analysed in the arm they were randomly assigned to) with non-responder imputation for categorical variables (eg, das28 remission, acr response), last observation carried forward until patient withdrawal for missing joint counts and no additional imputation of missing values."
1011,PMC3551223,S75,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,the target sample size (235 patients per arm) was computed to provide 80% power to detect a 12.5% treatment effect difference between an expected 42.5% das28 remission rate at week 24 in the add-on strategy arm versus 30% in the switch strategy arm.12
1012,PMC3551223,S76,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"this difference (12.5%) was deemed to be clinically relevant by the study's steering committee (see supplementary data, available online only)."
1013,PMC3551223,S77,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the following additional endpoints were analysed in accordance with the european league against rheumatism (eular)/acr collaborative recommendations for reporting ra disease activity in clinical trials:11
1014,PMC3551223,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"other outcome measures at week 24 included mean changes in das28–esr and in selected variables (eg, swollen joint count, tender joint count, esr, crp, haq–di, raqol); percentage of patients who improved during the 24 weeks of the study according to acr20/50/70/90, eular response and the percentage of patients with das28 <3.2 (low disease activity state)."
1015,PMC3551223,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"remission as defined by the 2010 acr–eular criteria (boolean definition),15 simplified disease activity index ≤3.3 and clinical disease activity index ≤2.8 were analysed post hoc."
1016,PMC3551223,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"to approach the concepts of onset of action and sustainability, changes over time of selected variables such as joint counts, crp, pain and haq–di were evaluated."
1017,PMC3551223,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,the domain fatigue was evaluated using question 21 of the raqol questionnaire.
1018,PMC3551223,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"radiographic endpoints included changes from baseline in total gss, erosion and joint space narrowing scores and the proportion of patients with no radiographic progression (progression defined as change in gss >sdc or >0)."
1019,PMC3551223,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"safety endpoints included the incidence of adverse events (ae), serious ae, serious infections and specific laboratory abnormalities, which were analysed in the safety population (all treated patients with at least one post-dose assessment of safety, analysed according to the treatment received)."
1020,PMC3590447,S41,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and participants,"in this randomised controlled trial, patients were recruited from 37 of 45 renal units in acute hospitals throughout the uk that obtained local ethical approval."
1021,PMC3590447,S42,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and participants,"inclusion criteria were: age 18–75 years; biopsy-proven diagnosis of membranous nephropathy (we did not impose a limit on the time since biopsy), regarded as idiopathic with no evidence of an underlying cause (such as drugs, infections, or tumours); and serum or plasma creatinine concentration of less than 300 μmol/l together with a 20% or greater decline in excretory renal function (measured by creatinine clearance or estimated with the cockcroft-gault calculation, and later by the modification of diet in renal disease [mdrd] formula13) that was based on at least three measurements over a period of 3 months or longer within the 2 years before study entry."
1022,PMC3590447,S43,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and participants,we excluded patients whose membranous nephropathy was a result of secondary causes (defined according to usual clinical practice).
1023,PMC3590447,S44,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and participants,"other exclusion criteria were: known infection with hepatitis b or c virus or hiv; known malignant disease; positive antibodies to double-stranded dna; current treatment with gold, penicillamine, non-steroidal anti-inflammatory drugs, cytotoxic drugs, or ciclosporin; more than 3 months' treatment with corticosteroids in the preceding 2 years; pregnancy or unreliable contraception; or a previous adverse reaction to prednisolone, methylprednisolone, chlorambucil or ciclosporin."
1024,PMC3590447,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and participants,ethics approval was obtained from the south west multicentre research ethics committee (reference mrec/97/6/12).
1025,PMC3590447,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and participants,each participating centre also obtained local ethical approval.
1026,PMC3590447,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and participants,all patients gave written informed consent.
1027,PMC3590447,S49,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,"eligible patients were randomly assigned by a member of staff in the clinical trials office at the glasgow royal infirmary, glasgow, uk, who was not otherwise involved in the trial."
1028,PMC3590447,S50,"['8a', '5', '8b']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 1, 1, 0]",Randomisation,"a random numbers table had been prepared to allocate patients to one of three groups: supportive therapy alone, supportive therapy plus 6 months of prednisolone and chlorambucil, or supportive therapy plus 12 months of ciclosporin."
1029,PMC3590447,S51,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,treatment allocation was communicated by fax to the clinician entering the patient into the trial.
1030,PMC3590447,S52,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,we did not attempt to mask patients or investigators.
1031,PMC3590447,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"we recorded baseline data for the supportive treatment alone group at randomisation, because these patients were effectively continuing their existing management."
1032,PMC3590447,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"in the two groups receiving immunosuppressive treatment in addition to supportive therapy, baseline data were recorded when the new treatment began."
1033,PMC3590447,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,we could not always start immunosuppressive treatment immediately after randomisation because the new treatments had to be prescribed and delivered.
1034,PMC3590447,S57,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,the treatment schedules were based on best available evidence at the time.
1035,PMC3590447,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"all patients received supportive therapy, including renin-angiotensin blockade, statins, and anticoagulants as indicated."
1036,PMC3590447,S59,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"those assigned to supportive therapy plus 6 months' prednisolone and chorambucil11 received intravenous methyl prednisolone 1 g per day for 3 consecutive days then oral prednisolone 0·5 mg/kg per day for 28 days during months 1, 3, and 5."
1037,PMC3590447,S60,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,intravenous prednisolone was administered in hospital.
1038,PMC3590447,S61,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"during months 2, 4, and 6, patients received oral chlorambucil at a starting dose of 0·15 mg/kg per day."
1039,PMC3590447,S62,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,we gave this reduced dose because the parent drug and its metabolites are renally excreted and our preliminary work14 had shown that a dose of 0·2 mg/kg per day was poorly tolerated in patients with impaired excretory renal function.
1040,PMC3590447,S63,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,we reduced the dose further if the patient developed leucopenia (weekly full blood counts were advised) and interrupted it if leucopenia was severe.
1041,PMC3590447,S64,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"those assigned to supportive therapy plus 12 months' of ciclosporin received a starting dose of 5 mg/kg per day,12 adjusted according to trough blood concentrations of the drug to achieve a concentration of 100–200 μg/l."
1042,PMC3590447,S65,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,we reduced the dose if toxicity was evident.
1043,PMC3590447,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"we followed up patients until they met the primary endpoint, or for a minimum of 3 years if they did not do so."
1044,PMC3590447,S67,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,the trial was not formally analysed until 3 years after all patients had begun treatment.
1045,PMC3590447,S68,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,all surviving trial patients remain under routine follow-up at their renal units.
1046,PMC3590447,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"the primary endpoint was a further 20% decline in excretory renal function from baseline readings, calculated in all patients with the cockcroft-gault equation (standard methodology at the start of the trial)."
1047,PMC3590447,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,secondary endpoints were proteinuria (measured with 24-h urinary collections or estimated from protein–creatinine ratios by multiplying the ratio [in mg/mmol] by 10) and severe adverse events.
1048,PMC3590447,S71,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,the primary investigator (pwm) identified which adverse events were serious and categorised them according to the most affected body system.
1049,PMC3590447,S72,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"we report all serious adverse events as defined by the medicines and healthcare products regulatory agency (mhra) guidance15—(ie, any adverse event, adverse reaction, or unexpected adverse reaction that results in death, is life-threatening, results in admission to hospital or extends the length of an existing hospital stay, results in persistent or serious disability or incapacity, or consists of a congenital anomaly or birth defect)."
1050,PMC3590447,S73,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,we also regarded as serious other important medical events that might have jeopardised the patient or needed intervention to prevent one of these outcomes.
1051,PMC3590447,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,we recorded information about deaths and development of end-stage renal disease.
1052,PMC3590447,S75,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"in accordance with the medical research council's guidelines for good clinical practice, a trial steering committee and a data monitoring committee were established to receive yearly reports for primary endpoints, adverse events, and deaths."
1053,PMC3590447,S77,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"to have 90% power to detect a reduction in frequency of the primary endpoint from 80% in the supportive treatment group to 40% in the immunosuppression groups with p<0·05, we calculated that 35 patients would be needed in each group (105 in total)."
1054,PMC3590447,S78,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"after allowing for an estimated dropout rate of 10%, we concluded that we needed to recruit 116 patients."
1055,PMC3590447,S79,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"primary analysis followed the principles of intention to treat, and secondary analysis assessed all patients who received at least one dose of treatment."
1056,PMC3590447,S80,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"unless otherwise stated, p values and estimates of treatment effects are based on two-way comparisons."
1057,PMC3590447,S81,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we did not make adjustments for multiple comparisons.
1058,PMC3590447,S82,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we analysed time to further 20% decline in renal function by the log-rank test and calculated hazard ratios [hrs] with cox proportional hazards regression.
1059,PMC3590447,S83,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we used the log-rank test for other survival endpoints, and repeated measures analysis of variance fowr continuous longitudinal data (eg, proteinuria)."
1060,PMC3590447,S84,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we analysed serious adverse event data with the log-rank test on the basis of time to first serious adverse event.
1061,PMC3590447,S85,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we did statistical analyses using sas software (version 9.2).
1062,PMC3590447,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"in 2003, the trial was shown to comply with the requirements of the eu clinical trials directive, and in 2004, a clinical trial authorisation (cta) was obtained from the medicines and healthcare products regulatory authority (cta number 18524/0001/001)."
1063,PMC3590447,S87,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"in 2008, the trial was adopted onto the national institute for health research portfolio and assigned the uk clinical research network identification number 2579."
1064,PMC3590447,S88,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"the trial is registered as an international standard randomised controlled trial, number 99959692."
1065,PMC3590447,S90,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,"the sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report."
1066,PMC3590447,S91,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding source,the corresponding author had full access to all the data in the study and had final responsibility to submit for publication.
1067,PMC3623038,S114,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,web supplement
1068,PMC3623038,S116,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,web figure
1069,PMC3623038,S118,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,web table
1070,PMC3623038,S28,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients and methods,the present randomised trial complied with the consort 2010 guidelines and was registered at clinicaltrials.gov (identifier: nct01108029).
1071,PMC3623038,S30,"['4a', '4b']","[0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"consecutive patients (diagnosed according to gibb's criteria9 and monitored at lille university hospital's pd clinic) were invited to participate in the study by cm, ad, ld and dd until the required number of participants was obtained."
1072,PMC3623038,S31,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients were enrolled between may 2010 and november 2010, following their provision of written, informed consent to participation."
1073,PMC3623038,S32,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,the research protocol was approved by the local independent ethics committee (protocol id: 2008-008210-38).
1074,PMC3623038,S33,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"the main inclusion criterion was the presence of a severe gait disorder (defined as a score ≥2 for updrs part iii item 29) and an abnormal, forward-leaning stance (a score ≥2 for item 28) despite optimal l-dopa treatment."
1075,PMC3623038,S34,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,the main exclusion criterion was the presence of axial disorders related to insufficient doses of l-dopa or off-periods of motor fluctuation or those induced by stn stimulation.
1076,PMC3623038,S35,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,patients receiving stn stimulation had to have shown an improvement of at least 50% in motor symptoms during the first year of this treatment (without a worsening in gait and posture).
1077,PMC3623038,S36,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,the appearance of axial signs immediately after the initiation of stn stimulation was also an exclusion criterion.
1078,PMC3623038,S37,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"other notable exclusion criteria included (i) inability to walk unaided while on dopaminergic treatment, (ii) dementia (diagnosed according to the dsm-iv-r criteria and with a mattis dementia rating scale score <130) and (iii) the ongoing administration of an nmda antagonist other than memantine."
1079,PMC3623038,S39,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Experimental design,"we performed a 90-day, double-blind, placebo-controlled pilot study."
1080,PMC3623038,S41,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,subjects were randomly assigned to memantine or placebo.
1081,PMC3623038,S42,"['8a', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Randomisation and masking,the 1 : 1 assignment sequence (based on a computer random-number generator) was produced by our department of biostatistics.
1082,PMC3623038,S43,"['11b', '10']","[0, 1, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"the randomisation list was sent to an independent contract research organisation (lc2, lentilly, france) for preparation and distribution of identical capsules of memantine and placebo."
1083,PMC3623038,S45,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Intervention,"patients, study staff and investigators were blinded to the assignment."
1084,PMC3623038,S46,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,"after a 30-day dose titration phase (with an increase of 5 mg of memantine per week or a placebo), the patients received a daily dose (at 7:00) of 20 mg of memantine (ie, the usual recommended dose) or placebo for a further 60 days."
1085,PMC3623038,S47,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,all patients undergoing stn stimulation were assessed under ‘on-stim’ conditions.
1086,PMC3623038,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,patients were not allowed to change their medication regimen or stn stimulation settings in the 3 months prior to the study or during the study itself.
1087,PMC3623038,S50,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy criteria,the primary efficacy criterion was the change in stride length (m) under ‘on-l-dopa’ conditions.
1088,PMC3623038,S51,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy criteria,"stride length was assessed in an optoelectronic analysis with a 6-camera vicon video system from oxford metrics (oxford, uk) (sampling rate: 50 hz)."
1089,PMC3623038,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy criteria,"secondary efficacy criteria included (i) gait velocity (m/s) and cadence (steps/min); (ii) motor handicap, assessed as the overall updrs motor score and its axial subscore (the sum of items 18 (speech), 19 (facial expression), 22 (neck rigidity), 27 (arising from a chair), 28 (posture), 29 (gait) and 30 (postural stability)); (iii) lid, assessed as the overall dyskinesia rating scale score and its axial subscore; (iv) hypertonia of axial flexors and extensors, assessed as the mean work (in joules) performed during 10 passive trunk movements at 30°/s on a con-trex isokinetic dynamometer (cmv ag, dübendorf, switzerland)10; (v) trunk flexor and extensor strength, measured as the mean work (in joules) performed over three repetitions at 30°/s in active flexion and extension mode on the isokinetic dynamometer.10"
1090,PMC3623038,S53,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy criteria,"all measurements were recorded in a double-blind manner in our hospital's gait laboratory by cm, ad and vt."
1091,PMC3623038,S55,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Standardised assessment,"efficacy criteria were assessed at 8:30 in the morning under ‘off-l-dopa’ conditions, that is, at least 8 h after the withdrawal of dopaminergic medications."
1092,PMC3623038,S56,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Standardised assessment,"after acute administration of l-dopa at 9:00, the ‘best on’ condition was assessed at between 9:30 and 10:00 on the same morning."
1093,PMC3623038,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Standardised assessment,all assessments were performed once before the 90-day course of study medication and once afterwards.
1094,PMC3623038,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Standardised assessment,"the l-dopa dose used in the assessment was 150% of the usual, first morning dose taken by patients to relieve their symptoms (table 1)."
1095,PMC3623038,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Standardised assessment,table 1 characteristics of the study population
1096,PMC3623038,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety criteria,"adverse events, arterial blood pressure values, an electrocardiogram and a standard blood biochemistry profile were recorded monthly."
1097,PMC3623038,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety criteria,"in view of a possible antagonistic effect of memantine on nicotinic acetylcholine receptors,5 drowsiness was assessed on the epworth sleepiness scale."
1098,PMC3623038,S63,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Safety criteria,the study's data and safety monitoring board examined adverse event reports periodically but the blinding code was not broken.
1099,PMC3623038,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety criteria,"in order to estimate the final plasma concentration of memantine, a blood sample was taken from all patients (ie, both groups, to maintain blinding) before the morning administration of study medication at 7:00 on the last day of treatment."
1100,PMC3623038,S66,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size calculation,"in a previous study of 17 patients on methylphenidate, we had observed a stride length increase (relative to baseline) of 0.4 m (sd: 0.4) in the stand-walk-sit test after 3 months of treatment.11"
1101,PMC3623038,S67,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size calculation,"despite our use of a more sensitive optoelectronic analysis in the present study, we adopted the same anticipated stride length difference, that is, 0.4 m (sd: 0.4)."
1102,PMC3623038,S68,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size calculation,"with a power of 80% and a type i error of 5%, the total sample size was found to be 17 patients per group."
1103,PMC3623038,S69,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size calculation,"next, on the basis of (i) a coefficient of 0.4 for the correlation between the baseline measurement and the end-of-study measurement in a covariance analysis, (ii) a very low dropout rate and (iii) the replacement of dropouts, we calculated the required sample size to be 14 patients per group."
1104,PMC3623038,S71,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,descriptive analyses and the shapiro-wilk test were used to check whether data were normally distributed.
1105,PMC3623038,S72,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,non-normally distributed data were log-transformed.
1106,PMC3623038,S73,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the primary criterion was tested in a covariance analysis (with adjustment for baseline) for all patients with data recorded in the final assessment.
1107,PMC3623038,S74,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the effect size was also computed.
1108,PMC3623038,S75,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"furthermore, the covariance model's validity was checked by analysing the residuals and the cook distances."
1109,PMC3623038,S76,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,numerical safety data for all randomised patients were assessed in an analysis of variance.
1110,PMC3623038,S77,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the threshold for statistical significance was set to p=0.05 in all cases.
1111,PMC3623038,S78,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all statistical tests were two-tailed and performed with sas software (v.9.2, sas institute inc., cary, north carolina, usa)."
1112,PMC3641608,S44,"['3a', '4a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,"arrow was an open-label randomised parallel-group trial in untreated (except for art to prevent mother-to-child-transmission) children or adolescents (aged 3 months to 17 years) with hiv who met who 2006 criteria for art initiation15 from three centres in uganda (joint clinical research centre, kampala; baylor-uganda, mulago; mrc/uvri uganda research unit on aids, entebbe), and one in zimbabwe (university of zimbabwe, harare)."
1113,PMC3641608,S45,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,"children with acute infections, on drugs contraindicated with art, unlikely to adhere or to attend regularly, with laboratory abnormalities contraindicating art, pregnant or breastfeeding, or perinatally exposed to art (if <6 months old) were excluded."
1114,PMC3641608,S46,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Trial design,participants were randomly assigned (1:1) to clinically driven monitoring versus routine laboratory plus clinical monitoring for toxicity (haematology and biochemistry) and efficacy (cd4).
1115,PMC3641608,S47,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Trial design,"children were also randomly assigned (1:1:1) in a factorial design to three approaches for first-line art: open-label lamivudine, abacavir, plus nnrti continuously (group a, control); induction-maintenance with four-drug lamivudine, abacavir, nnrti, plus zidovudine for 36 weeks, then lamivudine, abacavir, plus nnrti (group b); or induction-maintenance with lamivudine, abacavir, nnrti, plus zidovudine for 36 weeks, then lamivudine, abacavir, plus zidovudine (group c)."
1116,PMC3641608,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,hla testing was not done.
1117,PMC3641608,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,hiv viral loads were done retrospectively on stored samples.
1118,PMC3641608,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,the hypothesis was that clinically driven monitoring would result in similar outcomes to routine laboratory monitoring (non-inferiority) and that four-drug induction-maintenance would have greater efficacy than would standard three-drug art.
1119,PMC3641608,S51,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Trial design,the nnrti (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
1120,PMC3641608,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,caregivers gave written informed consent; older children (8–17 years) aware of their hiv status also gave assent or consent following national guidelines.
1121,PMC3641608,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,"the trial was approved by research ethics committees in uganda, zimbabwe, and the uk."
1122,PMC3641608,S55,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Randomisation and masking,"both factorial randomisations were stratified by centre and age (<7, 7–12, ≥13 years)."
1123,PMC3641608,S56,"['9', '8a']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 1]",Randomisation and masking,"the computer-generated sequentially numbered randomisation list (with variable block sizes) containing both allocations was pre-prepared by the trial statistician and incorporated within the secure database at each trial centre, connected to but not located within each clinical centre, allowing trial managers to access the next number, but not the whole list."
1124,PMC3641608,S57,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,randomisation was undertaken by clinicians phoning the local trials centre.
1125,PMC3641608,S58,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,"once randomised, allocation was open—ie, physicians and carers were aware of group assignment."
1126,PMC3641608,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"all participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (cd4, cd8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks."
1127,PMC3641608,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,screening results were used to assess eligibility.
1128,PMC3641608,S62,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"all subsequent results for participants assigned to routine laboratory monitoring were returned to clinicians, whereas results at and after randomisation for participants allocated clinically driven monitoring were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in dart,16 as were grade 4 laboratory toxicities (protocol safety criteria; grades defined17 apart from neutrophils18)."
1129,PMC3641608,S63,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"total lymphocytes and cd4 tests were never returned for participants on clinically driven monitoring, but for all children other investigations could be requested and concomitant drugs prescribed, as clinically indicated."
1130,PMC3641608,S64,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,all children received art as syrups or tablets dosed according to who weight-band tables.19–21
1131,PMC3641608,S65,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,children were reviewed every 4–6 weeks by a nurse using a standard symptom checklist.
1132,PMC3641608,S66,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"antiretroviral drugs could be substituted, preferably within class, after adverse events."
1133,PMC3641608,S67,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"during four-drug induction, a drug could be dropped because of toxicity or drug interactions with antituberculosis treatment."
1134,PMC3641608,S68,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"switching to second-line art (including a ritonavir-boosted protease inhibitor) was based on clinical criteria in all participants (new or recurrent who stage 4 event;15 or who stage 3 event or events at clinician discretion, particularly if recurrent or persistent), or on laboratory criteria for routine laboratory monitoring (confirmed on-art cd4 of <15% at age 1–2 years, <10% at 3–4 years, <100 cells/ml at ≥5 years)."
1135,PMC3641608,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,see appendix for further details.
1136,PMC3641608,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"co-primary endpoints for the monitoring randomisation were progression to new who stage 4 event or death (efficacy), and grade 3 or 4 adverse events not solely related to hiv (safety)."
1137,PMC3641608,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,co-primary endpoints for the art-strategy randomisation were change in cd4 percentage from randomisation to 72 and 144 weeks (efficacy) and grade 3 or 4 adverse events (safety).
1138,PMC3641608,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"secondary endpoints for both randomisations (if not co-primary) were: mortality; new (or new or recurrent) who stage 4 event or death; new (or new or recurrent) who stage 3 or 4 event or death; grade 3 or 4 adverse events definitely, probably, or uncertainly art-related; serious adverse events22 not solely hiv-related; art-modifying adverse events; admissions to hospital; height, weight, and body-mass index for age; cd4; number and class of antiretrovirals received; switch to second-line regimen; adherence; viral load and resistance (done retrospectively; see appendix)."
1139,PMC3641608,S73,"['6a', '11a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"all who stage 3 or 4 events, deaths, and serious adverse events were reviewed against prespecified criteria by an endpoint review committee with an independent chair and members, masked to randomised allocations."
1140,PMC3641608,S75,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"1200 children followed up for 3·5–5·0 years with less than 10% loss to follow-up provided 90% power to establish that clinically driven monitoring was not inferior to routine laboratory monitoring on the primary efficacy outcome, defined as the upper 95% confidence limit for the difference (clinically driven minus routine laboratory monitoring) in rate of first new who stage 4 event or deaths per 100 child-years being no greater than 1·6 per 100 child-years (assumed rate for routine laboratory monitoring of 2·5 per 100 child-years)."
1141,PMC3641608,S76,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"for the art-strategy randomisation, 1200 children provided 80% power to detect differences in change in cd4 percentage of more than 2·5% across the three groups (f test, two-sided α=0·05) assuming 20% missing data (loss to follow-up, missed visit or test) and standard deviation 10%.23"
1142,PMC3641608,S77,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Statistical analysis,interim data were reviewed annually by an independent data monitoring committee (four meetings) using the haybittle-peto criterion (p<0·001).
1143,PMC3641608,S78,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"randomised groups were compared with kaplan-meier plots, log-rank tests, and proportional hazards models, stratified by randomisation stratification factors (including the other factorial) for time-to-event disease progression, art, and adverse event outcomes, censoring at the earlier of trial closure or last follow-up."
1144,PMC3641608,S79,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,categorical variables were compared with χ2 or exact (if indicated) tests.
1145,PMC3641608,S80,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,change in cd4 percentage was compared with normal linear regression adjusted for randomisation stratification factors.
1146,PMC3641608,S81,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,laboratory measurements and adherence were compared across randomised groups over time with generalised estimating equations (independent correlation; closest measurement to each scheduled visit within equally spaced windows).
1147,PMC3641608,S82,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,all comparisons were as randomised (intention-to-treat).
1148,PMC3641608,S83,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"subgroups specified in the analysis plan were the factorial randomisations, time on art, sex, age, centre, cd4, weight for age, randomisation year, and previous art for prevention of mother-to-child transmission."
1149,PMC3641608,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,baseline values were those nearest to but before and within 42 days of randomisation.
1150,PMC3641608,S85,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,z scores were determined with the british reference because it covers the full age range of arrow children.24
1151,PMC3641608,S86,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,all analyses were done with stata 12.1.
1152,PMC3641608,S87,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,all p values are two-sided.
1153,PMC3641608,S88,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"this trial is registered, isrctn24791884."
1154,PMC3641608,S90,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding sources,"the sponsor (uk medical research council), other funders (uk department for international development), and viiv healthcare/glaxosmithkline (donated drugs; funded viral load assays) had no direct role in study design, data collection, analysis, interpretation, report writing, or the decision to submit for publication."
1155,PMC3641608,S91,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Role of the funding sources,the corresponding author had full access to all data and responsibility for submission for publication.
1156,PMC3668094,S34,"['3a', '5']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and sites,"this was a prospective, multicentre, double blinded, randomised trial of standard dose oseltamivir (75 mg twice a day or paediatric equivalent) versus double dose (150 mg twice a day or paediatric equivalent) for treating severe influenza."
1157,PMC3668094,S35,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and sites,"the study took place between april 2007 and february 2010 in 13 hospitals in indonesia, singapore, thailand, and vietnam."
1158,PMC3668094,S37,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"the inclusion criteria were age ≥1 year, respiratory illness with duration of symptoms ≤10 days, laboratory confirmed influenza, and either evidence of severe influenza (defined below) or positive result of a diagnostic test for h5n1."
1159,PMC3668094,S38,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"severe influenza was defined as admission to hospital and one of the following: new infiltrate on chest x ray; tachypnoea (respiratory rate ≥30 for ages ≥12, ≥40 for ages 6-11, ≥45 for ages 3-5, ≥50 for ages 1-2); dyspnoea; or hypoxia (arterial oxygen saturation ≤92% on room air)."
1160,PMC3668094,S39,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"exclusion criteria were pregnancy or positive for chorionic gonadotrophin (hcg) in urine, women who were actively breast feeding, a delay of more than 72 hours before treatment with oseltamivir, and severe renal impairment defined by creatinine clearance <10 ml/min (cockcroft-gault equation)."
1161,PMC3668094,S41,"['8a', '8b', '5']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 1, 1, 0]",Treatment,patients were randomised to receive double or standard dose oseltamivir based on a computer generated list that was stratified by site and age group.
1162,PMC3668094,S42,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Treatment,patients with h5n1 influenza were stratified separately.
1163,PMC3668094,S43,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,"oseltamivir capsules, paediatric oseltamivir suspensions, and placebo suspensions were provided by roche (basel, switzerland)."
1164,PMC3668094,S44,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,"placebo capsules were manufactured by the pharmaceutical development section at the national institutes of health clinical center (bethesda, md, us)."
1165,PMC3668094,S45,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,the doses were 75 mg or 150 mg twice daily in those aged ≥15 or weighing >40 kg; 60 mg or 120 mg twice daily in those weighing >23-40 kg; 45 mg or 90 mg twice daily in those weighing >15-23 kg; and 30 mg or 60 mg twice daily in those weighing ≤15 kg.
1166,PMC3668094,S46,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,these doses were halved for patients with a creatinine clearance ≥10 and <30 ml/min.17 19 20
1167,PMC3668094,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Treatment,all drug treatments were supervised by the research team.
1168,PMC3668094,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,all patients received five days of oseltamivir.
1169,PMC3668094,S49,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Treatment,"those with persistent tachypnoea, dyspnoea, or hypoxia on day five of the study were defined as meeting the criteria for clinical failure and continued to take the randomised dose for an additional five days."
1170,PMC3668094,S51,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study evaluations,"patients with severe influenza-like illness were screened with the quickvue rapid test (quidel, san diego, ca, us) and/or reverse transcriptase polymerase chain reaction (rt-pcr) of throat and nose swabs."
1171,PMC3668094,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study evaluations,patients with positive results for influenza virus who met the inclusion criteria were randomised.
1172,PMC3668094,S53,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study evaluations,swabs were obtained for virus detection in the nose and throat on days 0 to 10 and day 14.
1173,PMC3668094,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study evaluations,"study swabs were collected and eluted in m4 media (remel, lenexa, ks, us) before storage at −70 °c."
1174,PMC3668094,S56,"['6a', '11a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Virology,"testing of the combined nasal and throat swab specimens on day five, which was the primary virological study endpoint, was done under blinded conditions in the seaicrn reference laboratories in vietnam and indonesia."
1175,PMC3668094,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Virology,qualitative rt-pcr for detection of influenza a and b viruses and for subtyping of influenza a viruses was done according to who/us cdc protocols.21 22
1176,PMC3668094,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Virology,"quantitative rt-pcr for influenza virus a and b, with a lower limit of quantification of 103 copies of cdna per ml, was performed as described previously.23"
1177,PMC3668094,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Virology,virus culture and genotypic screening for oseltamivir resistance mutations were performed as described previously on day 0 samples for all enrolled patients and on day five samples for patients with positive results on rt-pcr.24 25
1178,PMC3668094,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Data analysis,the primary efficacy endpoint was the proportion of all patients with no detectable viral rna by rt-pcr in a combined nasal and throat swab sample on day five.
1179,PMC3668094,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Data analysis,"we also examined numerous secondary clinical endpoints (such as mortality, mechanical ventilation, admission to intensive care, symptoms, resumption of activity) and virological endpoints."
1180,PMC3668094,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Data analysis,we chose the proportion of patients with viral rna shedding at day five after the start of treatment as the primary endpoint as this represents the duration of one standard course of oseltamivir and clinical failure is generally evaluated after five days of treatment.
1181,PMC3668094,S65,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,this is also consistent with the 2010 position paper by ison and colleagues on the choice of efficacy endpoints in severe influenza studies.26
1182,PMC3668094,S67,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Data analysis,"based on previous studies, we assumed that children and adults admitted to hospital with influenza would have detectable virus for an average of 6.3 days (plus or minus 1.5 days) and 4 days after onset of treatment, respectively.26 27 28."
1183,PMC3668094,S68,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Data analysis,"if we assume that 30% of children and 55% of adults treated with standard dose oseltamivir would test negative for virus on day five, a sample size of 242 patients would be required to show a 20% absolute improvement in cessation of viral shedding with 85% power and a two sided α of 0.05."
1184,PMC3668094,S69,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Data analysis,"to allow for study withdrawals, our target sample size was 300 patients."
1185,PMC3668094,S71,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,"data were analysed with stata v10 (stata corporation, washington dc)."
1186,PMC3668094,S72,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,"the intention to treat population included all patients randomised, whether or not they received study drug."
1187,PMC3668094,S73,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,"for the virological endpoints, we included only patients with rt-pcr proved influenza virus infection on screening (day 0)."
1188,PMC3668094,S74,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,patients who died before day five were assumed to be virus positive on day five unless the virus was cleared before death.
1189,PMC3668094,S75,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,"for patients with missing results on day five, we carried forward the last available results."
1190,PMC3668094,S76,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,we used conditional univariate logistic regression to calculate and compare the odds ratios of viral clearance for categorical data between the treatment arms stratified by study site and the mantel-haenszel method when the numbers of patients were small.
1191,PMC3668094,S77,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,the breslow-day test was used to test the heterogeneity of the results between study sites.
1192,PMC3668094,S78,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,"because we found no heterogeneity, we used conditional multiple logistic regression to investigate independent predictors of viral rna clearance on day five, stratified by study sites."
1193,PMC3668094,S79,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,"in these regression models, the quantifiable viral load data were used (that is, ≥103 cdna copies/ml) and data from samples positive by qualitative rt-pcr but not quantifiable were given a value of 103 cdna copies(c)/ml, the lower limit of detection of the quantitative rt-pcr."
1194,PMC3668094,S80,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,this analysis was repeated by giving these samples the value of 0.
1195,PMC3668094,S81,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,"for multiple regression we forced important variables such as age group, (sub)type of virus, and treatment arm in the model, while for other factors we used forward stepwise variable selection procedure with 5% significance."
1196,PMC3668094,S82,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,normally distributed continuous data were compared between the two arms with the unpaired t test; the mann-whitney u or kruskal-wallis tests were used for skewed data.
1197,PMC3668094,S83,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,"for all comparative analyses, p<0.05 was considered significant."
1198,PMC3668094,S84,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,all p values are two tailed.
1199,PMC3668094,S85,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data analysis,confidence intervals for proportions and their differences were calculated with wilson’s method.
1200,PMC3686261,S35,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,data from patients enrolled in the premier trial9 were used for all analyses.
1201,PMC3686261,S36,"['3a', '5']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"premier was a 2-year, active-controlled, double-blind study of methotrexate-naive patients with early, progressive ra, in which patients were randomly assigned to the following treatment groups: combination treatment with subcutaneous adalimumab (40 mg every other week) and oral methotrexate (titrated to 20 mg/week by week 8, as tolerated), adalimumab monotherapy, or methotrexate monotherapy."
1202,PMC3686261,S37,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,employment outcomes were assessed in a large subset of patients who participated in the de032 companion study.19
1203,PMC3686261,S38,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"all patients provided written, informed consent, and the study protocols and informed consent forms were approved by the local institutional review boards or independent ethics committees at participating sites."
1204,PMC3686261,S39,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the studies were conducted in accordance with the principles of the declaration of helsinki and good clinical practice.
1205,PMC3686261,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient characteristics,"adults aged 18 years and older with an ra diagnosis, as defined by the 1987-revised american college of rheumatology criteria,20 were eligible for enrolment."
1206,PMC3686261,S42,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient characteristics,"patients must have satisfied the following inclusion criteria: disease duration less than 3 years, eight or more swollen joints (out of 66 assessed), 10 or more tender joints (out of 68 assessed), either an erythrocyte sedimentation rate greater than 28 mm/h or c-reactive protein (crp) concentration of 1.5 mg/dl or greater and either rheumatoid factor positivity or at least one je."
1207,PMC3686261,S43,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient characteristics,"patients were excluded if they had received previous treatment with methotrexate, cyclophosphamide, ciclosporin, azathioprine, more than two other disease-modifying antirheumatic drugs, or prednisone equivalent greater than 10 mg/day within 30 days of screening."
1208,PMC3686261,S45,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments","the 28-joint disease activity score with crp (das28(crp), range 0–10; hereafter referred to as das28) was used to monitor disease activity.21"
1209,PMC3686261,S46,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments",das28 was calculated at baseline and regular intervals to week 104.
1210,PMC3686261,S47,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments",a time-averaged das28 (ta-das28) was calculated in order to control for intergroup differences in speed of responses and longitudinal fluctuations in inflammation.
1211,PMC3686261,S48,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments","to obtain ta-das28, areas under the curve were determined for all time intervals of available das28 values from baseline to 52 or 104 weeks for individual patients."
1212,PMC3686261,S49,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments",values were summed and divided by the total time interval.
1213,PMC3686261,S50,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments",the distribution of ta-das28 values for all patients was then divided into tertiles at each assessment point.
1214,PMC3686261,S51,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments",radiographs of the hands and feet were taken at baseline and weeks 52 and 104.
1215,PMC3686261,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments","two readers, blinded to patient and sequence, scored radiographs individually for bone erosion (je, range 0–230) and jsn (range 0–168) using a modified form of the sharp scoring method (modified total sharp score; mtss).6 22–24"
1216,PMC3686261,S53,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments","physical function was evaluated using the haq-di at baseline, week 52 and week 104.25"
1217,PMC3686261,S54,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments",employment status (either employed or unemployed) was collected at baseline and at weeks 52 and 104.
1218,PMC3686261,S55,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]","Clinical, radiographic, functional and employment assessments","at each time point, a patient was asked if there was a change in employment status from the previous visit."
1219,PMC3686261,S57,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"descriptive analyses of changes in disease activity included observed data from patients who completed 52 or 104 weeks of treatment, had one or more post-baseline das28 and underwent radiography at baseline and weeks 52 or 104."
1220,PMC3686261,S58,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"analyses of the relationships between haq-di and je or jsn included observed data from patients with available haq-di, radiographic data and das28 at baseline, week 52, or week 104."
1221,PMC3686261,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"analysis of the relationships between employment status and je or jsn included observed data from patients with available employment status, radiographic data and haq-di at baseline, week 52, or week 104."
1222,PMC3686261,S60,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,overall mean changes from baseline in das28 were calculated at weeks 52 and 104 for the analysis population by treatment group.
1223,PMC3686261,S61,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"at weeks 52 and 104, the associations between ta-das28 tertiles and changes from baseline in je and jsn were compared for patients who received ada+mtx combination therapy, adalimumab monotherapy, or methotrexate monotherapy between and within treatment groups using an analysis of variance on the van der waerden normal scores.26"
1224,PMC3686261,S62,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"the relationships between haq-di and je or jsn at baseline, week 52 and week 104 were evaluated using quantile (non-parametric) regression models."
1225,PMC3686261,S63,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"each model evaluated the relationships between haq-di and either concurrent je or jsn as independent variables after covariate adjustment for concurrent das28 and baseline disease duration, age and sex."
1226,PMC3686261,S64,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"the relationships between employment status and je or jsn at baseline, week 52 and week 104 were evaluated using logistic regression models with covariate adjustment for concurrent haq-di and baseline disease duration, age and sex."
1227,PMC3686261,S65,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the relationship between baseline je or jsn and baseline employment status was further evaluated by calculating tertiles of je or jsn and determining the percentages of patients in each tertile who were employed at baseline; differences across je or jsn tertiles were evaluated through χ2.
1228,PMC3756454,S38,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,the study was performed with the approval of the local research ethics committee in accordance with the declaration of helsinki and with the written informed consent of all participants.
1229,PMC3756454,S39,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,inclusion criteria were a typical history of myocardial ischaemia lasting more than 20 min within 24 h of hospitalisation with ischaemic electrocardiographic changes and an elevated troponin-i concentration (>0.2 µg/l).
1230,PMC3756454,S40,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,"patients were excluded in the event of significant comorbidity, including active systemic inflammatory disorders, insulin-dependent diabetes mellitus and the use of anti-inflammatory drugs other than aspirin."
1231,PMC3756454,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,"given the immunosuppressive effects of etanercept, exclusion criteria also included any history of recent or recurrent infection, tuberculosis or any opportunistic infection within the previous 6 months."
1232,PMC3756454,S43,"['3a', '5']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"in a randomised, double-blind, parallel group design, patients were evaluated on two occasions: before and 24 h after intravenous administration of the tnf-α antagonist, etanercept (10 mg), or saline placebo."
1233,PMC3756454,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,a single subcutaneous 25 mg dose of etanercept improves endothelium-dependent vasodilatation within 6 h of administration in patients with heart failure.12
1234,PMC3756454,S45,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"in order to achieve a rapid onset of action, we elected to use the intravenous route, and single intravenous doses of up to 10 mg/m2 have been used safely in patients with heart failure.15"
1235,PMC3756454,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,subcutaneous etanercept has 23% bioavailability and achieves peak plasma concentrations of 0.43 µg/ml at 66 h.16
1236,PMC3756454,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"in contrast, a single intravenous dose of 10 mg etanercept achieves a maximum concentration of 2.32 µg/ml at 50 min.16"
1237,PMC3756454,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"given a plasma half-life of approximately 70 h,16 we judged that 24 h would be an appropriate time point to capture any potential beneficial cardiovascular effects of intravenous etanercept."
1238,PMC3756454,S49,"['8a', '9', '8b']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1]",Study design,"randomisation was performed by a computer generated sequence to ensure concealment of treatment allocation and following minimisation for age, sex, time to randomisation, peak troponin, serum cholesterol and cardiovascular risk factors including diabetes mellitus, hypertension and smoking.17"
1239,PMC3756454,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,study procedures were all completed prior to invasive angiography or percutaneous coronary intervention.
1240,PMC3756454,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Venous sampling and cytokine analysis,"patients abstained from food and caffeine containing drinks for 4 h, and 24 h from ingestion of alcohol prior to phlebotomy."
1241,PMC3756454,S53,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Venous sampling and cytokine analysis,"blood samples were obtained through a 17-gauge cannula with careful attention to ensure smooth extraction of blood to avoid artefactual platelet activation ex vivo, and anticoagulated with d-phenylalanyl-l-propyl-l-arginine chloromethyl-ketone (ppack)."
1242,PMC3756454,S54,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Venous sampling and cytokine analysis,"during vasomotor assessments, venous blood was withdrawn simultaneously from each arm and collected into tubes containing acidified buffered citrate (for t-pa assays), trisodium citrate (for plasminogen activator inhibitor type 1 (pai-1) assays) and potassium edta (for cytokine assays)."
1243,PMC3756454,S55,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Venous sampling and cytokine analysis,citrate and acidified buffered citrate samples were centrifuged at 2000 g for 30 min at 4°c and edta samples at 1000 g for 10 min at 20°c. platelet-free plasma was decanted and stored at -80°c before assay.
1244,PMC3756454,S56,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Venous sampling and cytokine analysis,"plasma tnf-α and il-6 concentrations were determined as described previously18 using elisa (quantikine human tnf and il-6 immunoassays, r&d systems; and dako a/s, respectively) and fibrinolytic activities using a photometric method (coatest t-pa and pai-1, chomogenix ab)."
1245,PMC3756454,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Venous sampling and cytokine analysis,haematocrit and white cell count were determined using an automated coulter counter (beckman-coulter).
1246,PMC3756454,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Vasomotor assessment,assessment of vasomotor function in response to intra-arterial vasodilators was performed as described previously.19
1247,PMC3756454,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Vasomotor assessment,"briefly, studies were performed in a quiet, temperature-controlled environment with the patient in the supine position throughout."
1248,PMC3756454,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Vasomotor assessment,venous 17-gauge cannulae were inserted into each forearm for blood sampling and a 27-standard wire gauge steel needle placed in the brachial artery of the non-dominant forearm for vasodilator infusions.
1249,PMC3756454,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Vasomotor assessment,"a baseline 30 min intra-arterial infusion of saline was followed by intra-arterial infusion of substance p at 2, 4 and 8 pmol/min; then acetylcholine at 5, 10 and 20 µg/min; and finally sodium nitroprusside at 2, 4 and 8 μg/min, infused for 10 min at each dose with each agonist separated by a 20 min saline infusion."
1250,PMC3756454,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Vasomotor assessment,forearm blood flow was measured in both arms by venous occlusion plethysmography with the use of mercury-in-silastic strain gauges.
1251,PMC3756454,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Vasomotor assessment,"heart rate and blood pressure in the non-infused arm were monitored at intervals throughout with the use of a semiautomated, non-invasive oscillometric sphygmomanometer."
1252,PMC3756454,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Immunostaining and flow cytometry,"all reagents were obtained from abd serotec (oxford, uk) unless otherwise stated."
1253,PMC3756454,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Immunostaining and flow cytometry,"the following antibodies were used: igg1-fitc, cd14-pe, cd42a-fitc, igg2a-pe, cd62p-pe, igg1-pe (ebioscience ltd. uk) and cd14-rpe and igg1-rpe (dakocytomation, denmark)."
1254,PMC3756454,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Immunostaining and flow cytometry,all antibodies were diluted 1:20 with flow buffer.
1255,PMC3756454,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Immunostaining and flow cytometry,"facs-lyse was obtained from becton-dickinson (cowley, uk)."
1256,PMC3756454,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Immunostaining and flow cytometry,blood anticoagulated with ppack was labelled with the appropriate antibodies exactly 5 min from collection and incubated in the dark for 20 min at room temperature.
1257,PMC3756454,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Immunostaining and flow cytometry,immunolabelling was performed on whole blood to avoid artefactual platelet activation caused by purification procedures.
1258,PMC3756454,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Immunostaining and flow cytometry,samples were then fixed and run through a facscalibur (becton-dickinson) flow cytometer within 2 h of fixing using an established flow protocol.20
1259,PMC3756454,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Immunostaining and flow cytometry,for determination of pma a total of 3000 events were collected in the cd14 monocyte gate.
1260,PMC3756454,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Immunostaining and flow cytometry,for platelet expression of p-selectin 7500 events were collected in the platelet gate.
1261,PMC3756454,S76,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data and statistical analysis,cytometric data analysis was performed with flowjo v.7.2.5 (flow cytometry analysis software).
1262,PMC3756454,S77,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data and statistical analysis,"plethysmographic data and net t-pa release were determined as described previously,19 21 as the product of the infused forearm plasma flow (based on the mean haematocrit and the infused fbf) and the concentration difference between the infused ([t-pa] inf) and non-infused ([t-pa] non-inf) arms: estimated net t-pa release=fbf×(1−hct)×([tpa]inf−[tpa]non-inf)."
1263,PMC3756454,S78,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data and statistical analysis,continuous variables are reported as means±sem.
1264,PMC3756454,S79,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data and statistical analysis,analysis of variance with repeated measures and a two-tailed student t test were performed as appropriate with the use of graphpad prism software.
1265,PMC3756454,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Data and statistical analysis,the primary outcome measure was pma.
1266,PMC3756454,S81,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Data and statistical analysis,on the basis of previous work examining the effect of clopidogrel on pma22 we estimated that a 5% absolute change in pma would be of clinical significance and that at least 12 paired samples would provide an 80% power to detect a 10% absolute difference in pma from baseline at a significance level of 5%.
1267,PMC4066691,S166,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,additional file 1: table s1
1268,PMC4066691,S167,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,adjusted mean differences in lung function and acq-7 score between tiotropium respimat® and placebo respimat®.
1269,PMC4066691,S168,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,click here for file
1270,PMC4066691,S42,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"this was a phase ii, randomised, double-blind, placebo-controlled, crossover study to investigate the efficacy and safety of three doses of once-daily tiotropium respimat®."
1271,PMC4066691,S43,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"the study was conducted in 19 sites in three european countries (germany, austria and ukraine; clinicaltrials.gov identifier nct01233284), and was carried out in accordance with the principles of the declaration of helsinki and the international conference on harmonisation good clinical practice guidelines."
1272,PMC4066691,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"all patients provided written, informed consent."
1273,PMC4066691,S46,"['5', '3a']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"after an initial screening visit and a 4-week run-in period, patients were randomised to one of four treatment sequences, during which they received each of the four treatments (tiotropium 5 μg, 2.5 μg or 1.25 μg or placebo, all delivered via the respimat® softmist™ inhaler) (figure  1)."
1274,PMC4066691,S47,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"each treatment was administered for 4 weeks, and there was no washout between treatment periods as pharmacodynamic steady state with tiotropium is known to be achieved after 3 weeks in chronic obstructive pulmonary disease [13,14]."
1275,PMC4066691,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,seven clinic visits were scheduled: at screening (visit 0); prior to the 4-week run-in (visit 1); at randomisation (after the 4-week run-in [visit 2]); every 4 weeks at the end of each treatment period (visits 3–6); and 21 days following the end of the final treatment period (visit 7).
1276,PMC4066691,S49,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,figure 1 study design.
1277,PMC4066691,S50,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,tiotropium respimat® (two puffs) or placebo respimat® (two puffs) was administered once daily in the evening between 18:00 and 20:00.
1278,PMC4066691,S51,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,all patients were required to continue maintenance treatment with stable medium-dose ics (400–800 μg budesonide or equivalent) for at least 4 weeks prior to visit 1 and until visit 7.
1279,PMC4066691,S52,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"patients using ics plus short-acting β2-agonist or ics + laba fixed-dose combinations were switched to the same dose of ics mono-product at least 8 or 24 hours, respectively, prior to visit 1."
1280,PMC4066691,S53,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,study medication was to be taken immediately after ics inhalation if normal ics dosing was in the evening.
1281,PMC4066691,S54,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,concomitant use of the following was not permitted for maintenance treatment: systemic oral or depot corticosteroids; anticholinergics other than tiotropium; labas; ics plus short-acting β2-agonist or ics + laba fixed-dose combinations; leukotriene modifiers; anti-immunoglobulin e treatment; chromone; methylxanthines; and phosphodiesterase-4 inhibitors.
1282,PMC4066691,S55,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,salbutamol hydrofluoroalkane metered-dose inhaler was provided by the sponsor as rescue medication for use as needed.
1283,PMC4066691,S56,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"permitted medication for the treatment of acute asthma exacerbations included salbutamol hydrofluoroalkane metered-dose inhaler, systemic corticosteroids and short-acting theophylline preparations."
1284,PMC4066691,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,each patient received all treatments.
1285,PMC4066691,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,eligible patients were randomly allocated to one of the four treatment sequences at visit 2 (figure  1).
1286,PMC4066691,S60,['8a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Study design,"the randomisation list was generated by boehringer ingelheim pharma gmbh & co. kg, biberach an der riss, germany, using a validated pseudo-random number generator and a supplied seed number."
1287,PMC4066691,S61,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Study design,"a fixed block randomisation, with a block size of 4, was used to ensure balanced and equal assignment."
1288,PMC4066691,S63,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study patients,"male or female patients aged 18–75 years, with at least a 3-month history of asthma at the time of enrolment and an initial diagnosis of asthma made before the age of 40 years, were included in the study."
1289,PMC4066691,S64,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study patients,"patients were required to have been on maintenance treatment with stable medium-dose ics (400–800 μg budesonide or equivalent), alone or in a fixed-dose combination with a laba or short-acting β2-agonist, for at least 4 weeks prior to visit 1."
1290,PMC4066691,S65,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study patients,"a diagnosis of asthma confirmed at visit 1 was required, with bronchodilator reversibility (15–30 minutes after 400 μg salbutamol) of ≥12% and ≥200 ml."
1291,PMC4066691,S66,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study patients,"patients were required to have a seven-question asthma control questionnaire (acq-7) mean score of ≥1.5 at visits 1 and 2, to have a pre-bronchodilator fev1 of ≥60% and ≤90% of predicted normal fev1 at visit 1, and to demonstrate absolute fev1 variability within 30% between visits 1 and 2."
1292,PMC4066691,S67,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study patients,"patients were required never to have smoked, or to be ex-smokers who had stopped smoking at least 1 year prior to enrolment and had a smoking history of less than 10 pack-years."
1293,PMC4066691,S68,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study patients,patients were excluded for any of the following reasons: a diagnosis of chronic obstructive pulmonary disease or any respiratory disease other than asthma; myocardial infarction within the last 6 months; hospitalisation due to cardiac failure or unstable cardiac arrhythmia within the past year; treatment with anti-immunoglobulin e antibodies within 6 months prior to visit 1.
1294,PMC4066691,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study end points,all end points were determined at the end of each 4-week treatment period (visits 3–6) and analysed as a response defined as change from study baseline (pre-treatment value measured at visit 2 in the evening).
1295,PMC4066691,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study end points,the primary efficacy end point was peak fev1 measured within the first 3 hours after dosing (peak fev1(0-3h)).
1296,PMC4066691,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study end points,"the following secondary efficacy end points were investigated: trough fev1; peak forced vital capacity (fvc) within the first 3 hours after dosing (fvc)(0-3h); trough fvc; fev1 area under the curve (auc) within the first 3 hours after dosing (fev1 auc(0-3h)); fvc auc(0-3h); pre-dose pefam and pefpm using the asthma monitor2+ device (am2+®; ert, philadelphia, pennsylvania, usa) based on the mean of the final week of each treatment period."
1297,PMC4066691,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study end points,"control of asthma, as assessed by acq-7 self-administered at the end of each 4-week treatment period, was an additional exploratory end point."
1298,PMC4066691,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study end points,"safety and tolerability were assessed based on the incidence and intensity of adverse events, and on changes in vital signs."
1299,PMC4066691,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study assessments,spirometric lung function tests were conducted at all in-clinic visits (visits 1–6).
1300,PMC4066691,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study assessments,pre-dose lung function tests were scheduled between 18:00 and 20:00.
1301,PMC4066691,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study assessments,"at visits 2–6, lung function tests were performed 10 minutes prior to and up to 3 hours after dosing of study treatment."
1302,PMC4066691,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study assessments,acq-7 was self-administered at visits 1–6 prior to lung function tests.
1303,PMC4066691,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study assessments,"measurement of pefam and pefpm was to be performed prior to ics and study treatment inhalation, at approximately the same time each day, from 06:00 to 08:00 for pefam and from 18:00 to 20:00 for pefpm."
1304,PMC4066691,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study assessments,adverse events and concomitant medications were recorded on the electronic case report form at each visit.
1305,PMC4066691,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study assessments,vital signs were measured and recorded in conjunction with lung function tests at visits 2–6.
1306,PMC4066691,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"efficacy data are reported for the full analysis set, which was defined as all randomised patients who were treated with at least one dose of study medication, had baseline data and had at least one on-treatment efficacy measurement after 4 weeks of treatment within a period."
1307,PMC4066691,S85,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"data are presented as adjusted mean change from baseline after 4 weeks of treatment (defined as response), unless noted otherwise."
1308,PMC4066691,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"evaluation of safety and tolerability was performed on the treated set, defined as all randomised patients who received at least one dose of study medication."
1309,PMC4066691,S87,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,analysis of adverse events and vital signs was descriptive in nature.
1310,PMC4066691,S88,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"to control the probability of a type i error in the primary efficacy analysis, stepwise testing of the null hypothesis was used to test the efficacy of tiotropium respimat® 5 μg, then 2.5 μg and then 1.25 μg, each over placebo respimat®."
1311,PMC4066691,S89,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"if the previous step was not successful, analysis of the current step was to be considered descriptive."
1312,PMC4066691,S90,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analyses,"to detect a treatment difference of 80 ml for peak fev1(0-3h) with 90% power, and assuming a standard deviation of 228 ml, it was calculated that 88 completed patients were required."
1313,PMC4066691,S91,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,testing was performed with α = 0.025 (one-sided).
1314,PMC4066691,S92,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the pre-specified hypotheses were tested using a mixed effects model with repeated measures.
1315,PMC4066691,S93,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the statistical model included ‘treatment’ and ‘period’ as fixed effects and ‘patient’ as a random effect.
1316,PMC4066691,S94,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"study baseline, defined as pre-treatment values measured at visit 2 in the evening, was included as covariate."
1317,PMC4085478,S100,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistics,"the sample size was increased from 30 to 36 patients per group to accommodate for nonresponse, loss to follow-up, and other deviations from planned study conditions."
1318,PMC4085478,S101,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"we also included dose groups of 0.8 and 1.6 g lt-02 to allow for dose-finding and dose-response analyses, as the drug lt-02 was new and had not been tested in studies."
1319,PMC4085478,S102,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,primary analysis was based on the full analysis set (intention to treat) that included all randomized patients.
1320,PMC4085478,S103,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"if a patient had a missing value at the final visit (v5), the latest available value was carried forward."
1321,PMC4085478,S104,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"analysis of covariance was used to model the primary end point, including the following baseline covariates: (i) mean sccai in the past 7 days of the screening period; and (ii) disease extent."
1322,PMC4085478,S105,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,the model including these two covariates and the treatment group effect was considered to be the core model.
1323,PMC4085478,S106,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"it was used to compare the effects of placebo and the individual dose groups in fixed sequence, starting with the highest dose group of 3.2 g lt-02 daily, followed by the lower dose groups in descending order."
1324,PMC4085478,S107,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"the confirmatory testing procedure stopped at the first nonsignificant result; superiority was given if the one-sided p value was <0.025, equivalent to a two-sided α level of 0.05."
1325,PMC4085478,S108,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,survival methods were used to analyze time-to-event variables; the log-rank test compared time with event curves between treatment groups.
1326,PMC4085478,S109,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,likelihood ratio χ2 tests based on nominal logistic regression were planned to compare the results of qualitative variables between treatment groups.
1327,PMC4085478,S110,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"the analysis plan did not specify how the groups should be compared: in order to increase the statistical power, we focused on the comparisons between placebo and the three active groups pooled."
1328,PMC4085478,S111,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,the statistical power to detect treatment effects in categorical parameters in this small sample size is far below the usual 80–90%.
1329,PMC4085478,S112,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"this is why we defined categorical variables such as rate of remission or mucosal healing a priori as secondary and exploratory, in order to discover trends in treatment effects to gather information for the sample-size calculation for future phase iii studies."
1330,PMC4085478,S113,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,linearity was checked for important continuous variables compared with log transformation.
1331,PMC4085478,S114,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,normality for continuous parameters was assumed if the absolute value of skewness was<1.
1332,PMC4085478,S115,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"in addition, the shapiro–wilk goodness-of-fit tests were applied."
1333,PMC4085478,S116,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Statistics,"a planned interim analysis was conducted by an independent data monitoring committee after half of the patients had terminated the treatment period to adjust the sample size or to stop the trial for futility, if indicated."
1334,PMC4085478,S117,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistics,"software for sample-size estimation included nquery advisor v5.0 (statistical solutions ltd, cork, ireland) and studysize v2.0 (creostat hb, v.frolunda, sweden)."
1335,PMC4085478,S118,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"statistical analyses were performed using sas jmp v9 and sas jmp v8 and higher (jmp, sas institute inc., cary, nc)."
1336,PMC4085478,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,figure 1 study flowchart.
1337,PMC4085478,S46,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"inclusion criteria were as follows: proven mesalazine-refractory ulcerative colitis (european consensus definition (16) with an inadequate response to mesalazine for 6 weeks at a dose of ≥3 g/day for over 4 weeks or documented intolerance to mesalazine (a documented intolerance required previous doctors' letters or medical notes that stated that an adverse event possibly related to mesalazine led to a discontinuation of its therapy); active disease with blood in stool for at least 6 weeks; sccai ≥5 and sccai subscore for “blood in stool” ≥2 at baseline visit (v2); comedication was allowed if on a stable dose for 4 weeks (e.g., 5-asa, systemic acting steroids (if taken for ≥8 weeks before the start of the study), azathioprine (2–2.5 mg/kg), 6-mercaptopurine (1–1.5 mg/kg), both if taken for ≥3 months); and a negative pregnancy test at v1 and v2 plus the use of adequate contraception, if applicable."
1338,PMC4085478,S47,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"exclusion criteria were as follows: toxic megacolon or fulminant courses; therapy with cyclosporine, tacrolimus, methotrexate, or tnf-α-antagonists within 3 months before study entry; current treatment with opiates or loperamide; current antibiotic treatment; rectal applications of aminosalicylates, steroids, or budesonide; oral application of topically acting steroids; ulcerative proctitis with a disease extent <10 cm; inflammatory or bleeding disorders of the gastrointestinal tract other than uc, or diseases that may cause diarrhea or gastrointestinal bleeding; condition after surgery of the colon; any other uncontrolled systemic diseases (e.g., cardiac, renal, pulmonary, hepatic) or severe chronic diseases (e.g., malignancies, hiv infection); and pregnant or nursing women."
1339,PMC4085478,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"5-asa, 5-aminosalicylic acid; ae, adverse event; discont."
1340,PMC4085478,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"intervent., discontinued intervention; inr, international normalized ratio; sccai, simple clinical colitis activity index; tnf-α, tumor necrosis factor-α uc, ulcerative colitis."
1341,PMC4085478,S50,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",METHODS,we calculated 160 patients with mesalazine-refractory uc for the screening phase in order to randomize 144 patients.
1342,PMC4085478,S51,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",METHODS,a planned interim analysis included the possibility of increasing the sample size if necessary.
1343,PMC4085478,S52,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"the main inclusion criteria were as follows: an active disease with the simple clinical colitis activity index (sccai) of ≥5 and a subscore for “blood in stool” of ≥2 at baseline; a history of bloody diarrhea for at least 6 weeks before inclusion despite mesalazine treatment at a dose of ≥3 g/day; or a documented intolerance to mesalazine (for details of criteria, see legend of figure 1)."
1344,PMC4085478,S53,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,patients were required to maintain a stable comedication throughout the study; steroid tapering was not allowed.
1345,PMC4085478,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,uc was defined in accordance with the european consensus conference (21).
1346,PMC4085478,S55,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"recruitment took place in 24 referral centers in germany, lithuania, and romania."
1347,PMC4085478,S56,"['8a', '8b', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",METHODS,the contract research organization (cro) produced computer-generated randomization lists for every study center with the allocation of 1:1:1:1 in blocks of 4.
1348,PMC4085478,S57,"['9', '5']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 1]",METHODS,"the study interventions consisting of three different doses of lt-02 (0.8, 1.6, and 3.2 g) were tested against placebo and were provided in sequentially numbered containers."
1349,PMC4085478,S58,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"doses were selected based on the results of the previous studies (18,19,20)."
1350,PMC4085478,S59,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,the study medication was provided in sachets with pellets taken orally four times daily.
1351,PMC4085478,S60,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,"the study medication was produced, packed, and labeled according to good manufacturing practice and stored at 2–8 °c."
1352,PMC4085478,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"patients were interviewed, examined, and screened for eligibility at the screening visit (v1, for inclusion and exclusion criteria see legend of figure 1)."
1353,PMC4085478,S62,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"patients to be included received detailed study information, gave written informed consent, and were instructed in completing the study diary (comprising sccai and other interview parameters)."
1354,PMC4085478,S63,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,stool samples were taken to exclude for infectious enterocolitis (including clostridium difficile and escherichia coli 0157:h7).
1355,PMC4085478,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",METHODS,"if the patient was still eligible after 1 week of screening (v2=baseline), a safety lab was taken and a sigmoidoscopy/colonoscopy was performed."
1356,PMC4085478,S65,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",METHODS,"at the interim visits 2 and 6 weeks after baseline (v3 and v4), possible disease exacerbation and changes in medication or adverse events (aes) were assessed."
1357,PMC4085478,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",METHODS,"the treatment period ended 12 weeks after baseline at v5 and involved an interview, a physical examination, a sigmoidoscopy, a safety lab, and the sccai assessment."
1358,PMC4085478,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",METHODS,the maximal duration of the study was 21 weeks per patient: a 1-week screening period plus 12 weeks of treatment period; patients reaching partial or complete remission (sccai <5 at end of treatment) underwent an additional 8-week follow-up without study medication (see appendix figure a1).
1359,PMC4085478,S68,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,patients could discontinue the study at any time without reason.
1360,PMC4085478,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,the investigator could withdraw a patient in case of aes or disease exacerbation or if therapeutic intervention was required.
1361,PMC4085478,S70,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",METHODS,"discontinuation criteria were the development of complications such as pseudomembranous colitis, an sccai increase of ≥7 over baseline, or fever >39 °c. discontinuation because of disease exacerbation was defined as an ae."
1362,PMC4085478,S71,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,patients who discontinued the study early qualified as “premature discontinuation” which resulted in a final study visit.
1363,PMC4085478,S72,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,dropouts were not replaced.
1364,PMC4085478,S73,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"patients' compliance was monitored by returned sachets, diary entries, and interviews."
1365,PMC4085478,S74,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,the central ethics committees approved the study protocol in all participating countries.
1366,PMC4085478,S75,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,no changes to the study methods were made after study initiation.
1367,PMC4085478,S77,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Precautions against bias,"to avoid selection bias, all patients who fulfilled all criteria were included into the study in the predefined, randomized order."
1368,PMC4085478,S78,['11b'],"[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Precautions against bias,"pellets, sachets, and containers were completely indistinguishable between treatment arms."
1369,PMC4085478,S79,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Precautions against bias,both patients and study personnel remained blinded and unaware of the allocation method throughout the study until database closure.
1370,PMC4085478,S80,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Precautions against bias,it was not possible for patients or investigators to guess the next allocated medication in order to avoid selection or allocation biases.
1371,PMC4085478,S81,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Precautions against bias,"to avoid attrition bias, we handled incomplete data in a conservative manner: all patients with premature treatment termination were included in all final analyses with their last available data (last observation carried forward (locf)), so that a possible lt-02 treatment effect was rather reduced than increased."
1372,PMC4085478,S82,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Precautions against bias,"more placebo patients may have stopped treatment owing to a lack of efficacy or for other reasons; it is unlikely that the results would have improved if treatment had been continued, and carrying forward the last value appeared to be conservative."
1373,PMC4085478,S83,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Precautions against bias,all dropouts and losses to follow-up are described in figure 1.
1374,PMC4085478,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Precautions against bias,individuals with possible conflict of interest were neither allowed to recruit patients nor were they involved in the conduct or analyses of the study.
1375,PMC4085478,S85,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Precautions against bias,there were no changes in the study methods or outcome parameters after study initiation.
1376,PMC4085478,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Precautions against bias,all authors had access to the study data and have reviewed and approved this manuscript.
1377,PMC4085478,S88,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,"the disease activity was assessed using the sccai (22) that is validated and has been proven to correlate well with other indices comprising invasive methods (23,24,25,26)."
1378,PMC4085478,S89,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the primary end point was changes in sccai from baseline (v2) to v5.
1379,PMC4085478,S90,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,"the sccai assesses stool frequency during the day and at night, defecation urgency, blood in stool, general well-being, abdominal pain, and extraintestinal manifestations."
1380,PMC4085478,S91,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,"the score ranges from 0 to 19 points—the lower the score, the lower the disease activity."
1381,PMC4085478,S92,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"we assessed the following secondary and a priori defined end points in an exploratory sense: complete remission (<3 mean sccai (26) and “blood in stool” subscore of 0 (see european crohn's and colitis organization (ecco) definition of remission (21), locf); partial remission (sccai <5, locf); clinical response (sccai decrease ≥2 (26); mucosal healing (endoscopic mayo score (ems) ≤1); achievement of mucosal healing (ems ≤1 at v5 and improvement of ems ≥1 from v2 to v5); patients with complete remission; and a “bowel frequency” subscore of 0."
1382,PMC4085478,S93,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,all sccai-based end points refer to the patient's mean values of 1 week rounded to integer numbers.
1383,PMC4085478,S94,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,time to symptom resolution was defined as the first 3 days with ≤3 stools per day without visible blood (21).
1384,PMC4085478,S95,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"the ems is categorized as follows: 0, inactive; 1, mild disease (erythema, decreased vascular pattern, minimal granularity); 2, moderate disease (marked erythema, friability, granularity, absent vascular pattern, bleeding on minimal trauma, no ulcerations); and 3, severe disease (ulceration, spontaneous bleeding)."
1385,PMC4085478,S96,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"the histologic index (by riley) ranges from 1 representing remission to 4 representing severe colitis; a central pathologist, who was blinded to the groups, assessed the score."
1386,PMC4085478,S98,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistics,data from a dose-finding study (19) showed that a relative effect size for the sccai of ∼0.8 could be expected from the 3.2 g dose group compared with placebo.
1387,PMC4085478,S99,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistics,"under the parametric assumptions of the t-test, 30 patients per group were needed to detect a difference of a relative effect size of 0.8 between placebo and an active group with a power of 85% (α=0.025, one sided)."
1388,PMC4145439,S196,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,web supplement
1389,PMC4145439,S40,"['3a', '4a']","[0, 0, 0, 0, 0, 0, 1, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"this was a 12-week, phase iib, dose-ranging, double-blind, placebo (pbo) and active-controlled, multicenter, randomised study (nct01242488), conducted between november 2010 and june 2012, to evaluate the efficacy and safety of subcutaneous okz in patients with moderately to severely active ra who had previously failed tnf inhibitor therapy."
1390,PMC4145439,S41,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the study protocol was approved by the institutional review board/independent ethics committee as defined in local regulations and performed according to the declaration of helsinki.
1391,PMC4145439,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,all patients provided written consent.
1392,PMC4145439,S43,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,the primary objective of the study was to evaluate the efficacy of okz at different doses and administration frequencies compared with pbo.
1393,PMC4145439,S44,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,"secondary objectives were to evaluate the safety, pharmacokinetics (pk), pharmacodynamics (pd) and immunogenicity of repeated doses of okz, and to assess the dose-response and exposure-response relationship of okz with efficacy."
1394,PMC4145439,S45,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design,an exploratory endpoint was to compare the efficacy and safety of okz with tcz.
1395,PMC4145439,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"of the 398 patients enrolled in the study, 221 were randomised to 1 of 9 treatment arms (figure 1)."
1396,PMC4145439,S47,"['10', '8a']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Study design,randomisation was performed centrally using an interactive voice-response system.
1397,PMC4145439,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"patients received either pbo or okz (60, 120 or 240 mg) every 4 weeks (q4w) or every 2 weeks (q2w), or 8 mg/kg tcz q4w."
1398,PMC4145439,S49,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"doses were selected in order to cover 35–75% of the maximal anticipated effect on das28(erythrocyte sedimentation rate, esr) at 12 weeks, or 45–85% of the maximal anticipated effect at 24 weeks, based on pk/pd analysis of previous study data.19 20"
1399,PMC4145439,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,figure 1 patient disposition.
1400,PMC4145439,S51,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Study design,randomisation was stratified according to the number of prior failed tnf inhibitors (1 vs 2 or more).
1401,PMC4145439,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,two safety follow-up visits were undertaken 6 and 12 weeks after the last study dose.
1402,PMC4145439,S53,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"to maintain blinding of the treatment, all patients received an intravenous infusion q4w and two 1.2 ml subcutaneous injections q2w."
1403,PMC4145439,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"tcz dose is the approved dose in europe by the ema,21 and the highest dose approved by the us food and drug administration (fda).18"
1404,PMC4145439,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,patients who completed the study were eligible to receive okz in an open-label extension study (nct01296711).
1405,PMC4145439,S57,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"this study population were individuals with active ra and an inadequate response to mtx, and at least one previous anti-tnf therapy."
1406,PMC4145439,S58,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients were ≥18 years old, with adult-onset ra of at least 6 months duration (1987 american college of rheumatology (acr) classification criteria22) or a score of ≥6 by the acr/european league against rheumatism (eular) classification and diagnostic criteria for ra.23"
1407,PMC4145439,S59,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"eligible patients had tender joint count ≥6 (tjc; assessment of 68 joints) and swollen joint count ≥6 (sjc; assessment of 66 joints) and crp ≥1.2 times the upper limit of normal (uln), or esr >28 mm/h."
1408,PMC4145439,S60,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,patients were required to be on a stable dose of mtx and continued current steroids and nsaids.
1409,PMC4145439,S61,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"major exclusion criteria included diagnoses of other inflammatory arthritis or a non-inflammatory type of arthritis that interfered with efficacy evaluations, functional capacity steinbrocker class iv,24 and prior exposure to il-6 inhibitors."
1410,PMC4145439,S62,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,patients were not permitted to use dmards other than mtx within 12 weeks prior to screening (unless undertaking appropriate washout).
1411,PMC4145439,S63,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients with a known risk of severe or major infections, or elevated levels at screening of creatinine, alanine aminotransferase (alt) or aspartate aminotransferase (ast), or reduced platelets, white blood cell count or neutrophil count were excluded."
1412,PMC4145439,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy analyses,"efficacy outcomes were assessed in the full analysis set (fas), consisting of all randomised patients who received at least one dose of study medication and had at least one post-baseline efficacy measurement."
1413,PMC4145439,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy analyses,the primary efficacy endpoint was the change from baseline in das28(crp) at week 12.
1414,PMC4145439,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy analyses,"secondary efficacy endpoints were acr20, acr50 and acr70 at week 12 for okz and pbo."
1415,PMC4145439,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy analyses,"major exploratory analyses included: acr20/50/70 response rates (at weeks 1, 2, 4, 6, 8, 10 and 12), % of patients with das28(crp) <2.6 at weeks 2, 4, 8 and 12), tjc, sjc, clinical disease activity index (cdai) and the health assessment questionnaire-disability index (haq-di)."
1416,PMC4145439,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety,safety assessments included measurement of vital signs and laboratory parameters as well as recording of treatment-emergent adverse events (teaes) and serious teaes.
1417,PMC4145439,S71,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Safety,"safety variables were analysed using the safety set (ss) (all patients who received at least 1 dose, or partial dose, of study medication)."
1418,PMC4145439,S73,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"unless specifically stated, fas was used for all analyses."
1419,PMC4145439,S74,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,das28(crp) was analysed using a mixed effects model for repeated measures (mmrm).
1420,PMC4145439,S75,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,acr20/50/70 responder rates were estimated using generalised estimating equation (gee) methodology with multiple imputation (mi).
1421,PMC4145439,S76,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,missing data for sjc/tjc/haq-di/cdai change from baseline were imputed using last observation carried forward (locf).
1422,PMC4145439,S77,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,non-responder imputation was used for analysis of % patients with das28(crp) <2.6 to control for missing values.
1423,PMC4145439,S78,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the number of prior failed tnf inhibitors was included as a categorical covariate in all statistical analyses.
1424,PMC4145439,S79,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"unless otherwise stated, all statistical tests were two-sided."
1425,PMC4145439,S80,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analyses,"power and sample size calculations were based upon simulations for change from baseline in das28 at all assessed postbaseline visits, using the mmrm method specified for the primary efficacy analysis."
1426,PMC4145439,S82,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Pharmacokinetic/pharmacodynamic analyses,"blood samples for determination of plasma okz, tcz and anti-okz antibodies were collected at baseline and at each subsequent visit."
1427,PMC4145439,S83,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Pharmacokinetic/pharmacodynamic analyses,non-linear mixed modelling was employed for the analysis of the okz pk data.
1428,PMC4145439,S84,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Pharmacokinetic/pharmacodynamic analyses,the final population pk model was used to derive individual concentration or exposure measures for use in the pk/pd analyses which involved describing the relationship between pk measures and multiple efficacy and safety endpoints via mixed effects methodology.
1429,PMC4145444,S40,"['4a', '4b']","[0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,children with active rickets were identified using radiographs of the wrists and the knees from among children who presented with leg deformities to the primary care setting of the family medicine department of the jos university teaching hospital in the geographic centre of nigeria (10° north latitude).
1430,PMC4145444,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,children were eligible for enrolment if they had a radiographic score of at least 2.5 on a validated 10-point scoring method that assessed the severity of rickets in the growth plates of the distal radius and ulna and around the knee.5
1431,PMC4145444,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,"approval for the study was obtained from the ethical committee of the jos university teaching hospital and the institutional review board of mayo clinic, and written informed consent was obtained from a parent of each enrolled child."
1432,PMC4145444,S43,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,"data were collected regarding symptoms of rickets, the frequency and quantity of dairy product intake, and usual sunlight exposure."
1433,PMC4145444,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,the percentage of unclothed skin at enrolment was estimated with a lund and browder age-related burn chart.
1434,PMC4145444,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,standing height was measured with a wall-mounted stadiometer.
1435,PMC4145444,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,"two 24-h dietary recalls were obtained on separate days to determine energy, phosphorus and calcium intake."
1436,PMC4145444,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,energy and mineral intakes were calculated using food composition tables for african foods.6–8
1437,PMC4145444,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,weight was measured with a hanging weighing scale.
1438,PMC4145444,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,"anthropometric z-scores were calculated with epi info 3.2.2 (cdc, atlanta, georgia, usa)."
1439,PMC4145444,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Subjects,all children were examined for clinical signs of rickets.
1440,PMC4145444,S51,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Subjects,"dual energy x-ray absorptiometry of the left distal and proximal 1/3 forearm was performed by a single investigator (tdt) with a portable densitometer (norland pdexa, model 476a110)."
1441,PMC4145444,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Subjects,"the densitometer had a short-term in vivo precision of 6.4% for areal bone density at the distal radius and ulna, and 7.2% at the proximal 1/3 radius and ulna, and a long-term in vitro precision of 1.1%."
1442,PMC4145444,S54,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,all children were treated with calcium carbonate as powdered limestone.
1443,PMC4145444,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Intervention,powdered limestone was locally available at a much lower cost than calcium tablets.
1444,PMC4145444,S56,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,"the content of elemental calcium in 1.0 g of limestone was 268 mg (courtesy of michael gruzak, usda/ars children's nutrition research center, houston, texas, usa)."
1445,PMC4145444,S57,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Intervention,samples of limestone had no toxic concentrations of heavy metals.
1446,PMC4145444,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,one level teaspoon of powdered limestone (approximately 3.5 g=938 mg of elemental calcium) was mixed with the child's food or porridge twice daily.
1447,PMC4145444,S59,"['8b', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Intervention,"enrolled children were randomised by coin toss (performed by tdt) to receive under direct observation either oral vitamin d2 as 50 000 iu (ergocalciferol; pliva, inc., east hanover, new jersey) once every 4 weeks (ca+d group) or placebo, which was a single vitamin b complex tablet, once every 4 weeks (ca group) for 24 weeks."
1448,PMC4145444,S60,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Intervention,subjects returned every 4 weeks for their supplements and assessment of adverse events.
1449,PMC4145444,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Intervention,the weight of limestone remaining at each visit was recorded to assess adherence.
1450,PMC4145444,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Intervention,"height, weight, venous blood, wrist and knee radiographs, and forearm bone density measurements were obtained at baseline and at 12 and 24 weeks after enrolment."
1451,PMC4145444,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Intervention,serum samples were stored at −20°c until transported frozen to the mayo clinic for analysis.
1452,PMC4145444,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Intervention,"serum calcium, phosphorus, alkaline phosphatase and albumin were measured with standard methods."
1453,PMC4145444,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Intervention,serum 25(oh)d was measured by isotope-dilution liquid chromatography–tandem mass spectrometry (lc-ms/ms).9
1454,PMC4145444,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Intervention,"unless otherwise indicated by subscript notation for individual metabolites, 25(oh)d refers to the total concentrations of 25(oh)d2 and 25(oh)d3."
1455,PMC4145444,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Intervention,concentrations of 25(oh)d below the limit of detection (5 nmol/l for 25(oh)d3 and 10 nmol/l for 25(oh)d2) were designated as zero for the data analysis.
1456,PMC4145444,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,the primary outcome was the combined attainment of a radiographic score of 1.5 or less and a serum alkaline phosphatase concentration of 350 u/l or less.
1457,PMC4145444,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,all radiographs were scored independently by two of the authors (tdt and prf) and the mean score was used for analysis.
1458,PMC4145444,S71,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"based on the primary outcome measures of radiographic score and serum alkaline phosphatase values and sds based on previous studies (1.6 for radiographic score and 150 u/l in alkaline phosphatase), 40 subjects in each treatment group would provide 80% power and 95% ci to detect a difference between groups of 1.0 in final radiographic score and 100 u/l in alkaline phosphatase."
1459,PMC4145444,S72,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"data analysis was performed with excel 2003 (microsoft corp., redmond, washington, usa) and jmp v.9.0.1 (sas institute inc., cary, north carolina, usa)."
1460,PMC4145444,S73,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"unless otherwise noted, means and sds are reported for continuous variables with normal distributions, and medians are reported for non-normally distributed variables."
1461,PMC4145444,S74,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"a paired t-test was used to compare values of continuous normally distributed variables with baseline values, and an unpaired t-test was used to compare values of continuous variables between groups."
1462,PMC4145444,S75,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the wilcoxon test was used to compare non-normally distributed variables.
1463,PMC4145444,S76,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,logistic regression was used to assess the effect of treatment group on the primary outcome while controlling for baseline group differences and to test for interactions between variables.
1464,PMC4145444,S77,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,p values less than 0.05 were considered significant.
1465,PMC4213545,S37,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"this phase 3, randomized, double-blind study in patients with moderate to severe copd was conducted in 222 centers throughout north america, australia, and new zealand (nct01437397) in accordance with the international conference on harmonization/good clinical practice guidelines and the declaration of helsinki."
1466,PMC4213545,S38,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"the protocol was approved by the institutional review board at each study center, and all patients gave written informed consent before participating in any study procedures."
1467,PMC4213545,S39,"['11a', '3a']","[0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the study comprised a 2- to 3-week run-in period prior to a 24-week double-blind treatment period (figure 1).
1468,PMC4213545,S40,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"patients were equally randomized to twice-daily aclidinium/formoterol fdc 400/12 μg, aclidinium/formoterol fdc 400/6 μg, aclidinium 400 μg, formoterol 12 μg, or placebo, administered via a multidose, dry-powder inhaler (genuair®/pressair®)*."
1469,PMC4213545,S41,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"the first patient/first visit was october 4, 2011 and the last patient completed february 6, 2013."
1470,PMC4213545,S42,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,figure 1 study design.
1471,PMC4213545,S43,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"acl400/for12 fdc, fixed-dose combination of aclidinium 400 μg and formoterol 12 μg; acl400/for6 fdc, fixed-dose combination of aclidinium 400 μg and formoterol 6 μg; d, day; wk, week."
1472,PMC4213545,S45,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients aged ≥40 years were eligible if they were current or former smokers (≥10 pack-years) and diagnosed with stable, moderate to severe expiratory airflow obstruction according to gold guidelines (postbronchodilator forced expiratory volume in 1 second [fev1]/forced vital capacity [fvc] <70% and fev1 ≥30% and <80% predicted) [1]."
1473,PMC4213545,S46,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"main exclusion criteria were: copd exacerbation or respiratory tract infection ≤6 weeks (≤3 months if hospitalized for exacerbation) before screening; clinically significant respiratory conditions (including asthma); clinically significant cardiovascular (cv) conditions including myocardial infarction (mi) within the previous 6 months; unstable angina; and, unstable arrhythmia that required changes in pharmacological therapy or other intervention within the previous 6 months."
1474,PMC4213545,S47,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,use of long-acting bronchodilators other than investigative treatment was not permitted.
1475,PMC4213545,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,"other copd medications, such as theophylline, inhaled corticosteroids (ics), oral or parenteral corticosteroids (≤10 mg/day or 20 mg every other day of prednisone) were allowed if treatment was stable ≥4 weeks prior to screening."
1476,PMC4213545,S49,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,use of albuterol/salbutamol as rescue medication was permitted.
1477,PMC4213545,S51,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and assessments,"coprimary efficacy parameters, assessed by standardized spirometric measurements of lung function [14], were change from baseline to week 24 in 1-hour morning postdose fev1 (each fdc versus aclidinium, contribution of formoterol) and change from baseline to week 24 in morning predose (trough) fev1 (each fdc versus formoterol, contribution of aclidinium)."
1478,PMC4213545,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and assessments,secondary efficacy parameters were change from baseline in st. george’s respiratory questionnaire (sgrq) total score at week 24 (each fdc versus placebo) and improvement in transition dyspnea index (tdi) focal score at week 24 (each fdc versus placebo).
1479,PMC4213545,S53,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and assessments,additional treatment comparisons for each coprimary parameter included: each aclidinium/formoterol fdc dose versus each monotherapy; each active treatment versus placebo; and aclidinium/formoterol fdc 400/12 μg versus aclidinium/formoterol fdc 400/6 μg.
1480,PMC4213545,S54,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and assessments,"additional efficacy parameters included: change from baseline in peak fev1 at all visits; 12-hour spirometry measurements (in a subset of the intention-to-treat [itt] population) based on change from baseline in fev1 at all study visits; sgrq and baseline/transition dyspnea index (bdi/tdi) at all study visits except week 24; rescue medication use; onset of action of bronchodilation; and, daily copd symptoms assessed by the exacerbations of chronic pulmonary disease tool (exact)-respiratory symptoms (e-rs) questionnaire [15]."
1481,PMC4213545,S55,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and assessments,"a nighttime symptoms of copd instrument (nisci) [16,17] and an early morning symptoms of copd instrument (emsci) [18]—newly developed patient reported outcome measures undergoing empirical testing—were completed twice daily by patients using the electronic diary."
1482,PMC4213545,S56,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and assessments,"safety was assessed through reporting of adverse events (aes), clinical laboratory tests, vital signs, electrocardiograms (ecgs), and 24-hour 12-lead holter monitoring."
1483,PMC4213545,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and assessments,"major adverse cardiovascular events (mace) were defined as the composite of cv deaths, nonfatal mis, and nonfatal strokes."
1484,PMC4213545,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and assessments,mace were evaluated and classified by an adjudication committee of independent cardiologists who were not participating in the study and were blinded to treatment.
1485,PMC4213545,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and assessments,"to identify all mace, a list of all aes that were reported in randomized patients based on standard medical dictionary for regulatory activities (meddra) queries of cardiac disorders and cerebrovascular disorders was used."
1486,PMC4213545,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes and assessments,assessments for all efficacy and safety outcomes occurred at various timepoints throughout the study (additional file 1: table s1).
1487,PMC4213545,S62,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,statistical analyses were performed using sas® version 9.2.
1488,PMC4213545,S63,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all efficacy analyses with the exception of e-rs were based on the itt population, defined as all randomized patients who took ≥1 dose of study medication and had a baseline and at least one postbaseline fev1 assessment."
1489,PMC4213545,S64,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"e-rs data were analyzed for the itt-exacerbation population, which included all patients in the randomized population who took at least 1 dose of double-blind investigational product."
1490,PMC4213545,S65,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"change from baseline in bronchodilation outcomes were analyzed by mixed model for repeated measures (mmrm) with treatment group, sex, smoking status, visit, and treatment-group-by-visit interaction as fixed-effect factors and corresponding baseline values and age as covariates, and pre- and postbronchodilator fev1 as a covariate for fev1 outcomes."
1491,PMC4213545,S66,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"a sample size of 1550 (310 per randomized group) was estimated to provide at least 90% power to detect a statistically significant treatment difference of 100 ml (standard deviation of 280 ml) between each fdc dose versus aclidinium monotherapy in change from baseline at 1-hour morning postdose fev1 at week 24, and 65 ml (standard deviation of 240 ml) between each fdc dose versus formoterol monotherapy in the change from baseline in morning predose (trough) fev1 at week 24."
1492,PMC4213545,S67,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"to control for family-wise type 1 error rate at the 2-sided 5% significance level for the primary and secondary efficacy endpoints, a prespecified multiple comparison strategy was conducted."
1493,PMC4213545,S68,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"the onset of action of bronchodilation in fev1 (an additional endpoint defined as a >15% increase from baseline in fev1) from 5-minutes to 3-hours postdose on day 1 was evaluated using a logistic regression model with treatment groups, sex, and smoking status as fixed-effect factors and pre- and postbronchodilator fev1 at screening, age, and baseline fev1 as covariates."
1494,PMC4213545,S69,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,odds ratios were estimated for each treatment group versus placebo.
1495,PMC4213545,S70,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,change from baseline in tdi and sgrq were analyzed using a mmrm as described for bronchodilation outcomes.
1496,PMC4213545,S71,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,a logistic random-effect model was used to analyze the number and percentage of patients who achieved a clinically meaningful improvement from baseline in sgrq total score (decrease of ≥4 units) [19] or in tdi focal score (increase of ≥1 unit).
1497,PMC4213545,S72,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,use of rescue medication was analyzed using averages of the daily diary values over the time periods between visits and were based on the change from baseline values.
1498,PMC4213545,S73,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"daily copd symptoms were analyzed by means of an mmrm adjusted for baseline, treatment, visit, sex, age, smoking status, and treatment-by-visit interaction."
1499,PMC4213545,S74,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"safety results, summarized descriptively, were based on the safety population, defined as all randomized patients who took ≥1 dose of study medication."
1500,PMC4215282,S100,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"briefly, linear, linear in log-dose, emax, sigmoid emax, logistic and exponential models were evaluated using multiple comparisons, and the data were fitted using the model with either the smallest akaike information criteria for normally distributed data or maxt for count data."
1501,PMC4215282,S101,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"to assess the precision of the model fitting, a bootstrap simulation was performed using 1000 iterations."
1502,PMC4215282,S102,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the cumulative number of new or enlarging non-enhancing t2 lesions at weeks 12–24 and the cumulative number of cuals at weeks 12 to 24 were analysed using the same statistical model and in the same patient analysis set as for the primary endpoint.
1503,PMC4215282,S103,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the time to first confirmed relapse was analysed using the kaplan–meier method.
1504,PMC4215282,S104,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the treatment effect versus placebo was described by hrs and the 95% cis derived from a proportional hazards model.
1505,PMC4215282,S105,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,total lymphocyte counts were summarised for the all-treated analysis set (all randomised patients who received at least one dose of study drug); the absolute values and changes from baseline to scheduled visits and to eot (last available value) were summarised by descriptive statistics.
1506,PMC4215282,S106,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,aes and saes were reported and summarised throughout the treatment and safety follow-up periods for the all-treated analysis set.
1507,PMC4215282,S107,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analyses,the underlying assumption for the sample size calculation was a 50% decrease in the mean cumulative number of new gd+ lesions from weeks 12 to 24 in at least one ponesimod treatment group compared with placebo and assuming a mean of eight lesions under placebo; the anticipated sample size of 90 evaluable patients per group had a 90% power to detect a significant difference between ponesimod groups and placebo.
1508,PMC4215282,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"eligible patients were men and women aged 18–55 years with rrms (as defined by the revised 2005 macdonald criteria15) and an expanded disability status scale (edss) score of 0–5.5, with at least one of the following characteristics: ≥1 documented relapse(s) within the 12 months before screening; ≥2 documented relapses within the 24 months before screening or at least one t1-weighted gadolinium-enhanced (gd+) lesion detected on brain mri at screening."
1509,PMC4215282,S42,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"study exclusion criteria were use of systemic corticosteroids within 30 days of randomisation; use of immunomodulators (interferon β, glatiramer acetate) and some immunosuppressants (cyclosporine, sirolimus and mycophenolic acid) within 3 months of randomisation; use of other immunosuppressants (azathioprine, methotrexate and natalizumab) and non-lymphocyte-depleting biologic agents (eg, daclizumab) within 6 months prior to randomisation."
1510,PMC4215282,S43,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients treated at any time with certain immunosuppressive (cyclophosphamide, mitoxantrone and cladribine) or lymphocyte-depleting biological agents (alemtuzumab and rituximab) were excluded from the study."
1511,PMC4215282,S45,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"this was a prospective, multicentre and multinational (94 centres in 23 countries, including europe, australia, canada and usa), randomised, double-blind, placebo-controlled, four-arm, parallel-group, dose-finding phase iib study, conducted in accordance with the declaration of helsinki16 and adhering to the international conference on harmonisation guidelines for good clinical practice.17"
1512,PMC4215282,S46,"['8b', '5']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 1, 0]",Study design and procedures,"within each investigation site, patients were randomised in a 1:1:1:1 ratio to once-daily treatment with placebo or ponesimod 10, 20 or 40 mg for 24 weeks."
1513,PMC4215282,S47,"['8a', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Study design and procedures,"patients were randomised by assignment of a unique randomisation number using an interactive voice or web response system, supplied by an independent service provider (icon clinical, research, usa)."
1514,PMC4215282,S48,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Study design and procedures,patient randomisation was stratified by centre using a block size of four for the first two blocks and eight thereafter.
1515,PMC4215282,S49,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"the primary investigator/treating neurologist, independent evaluating neurologist, physician evaluating cardiac safety assessments, care providers, patients and sponsor were blinded to the treatment."
1516,PMC4215282,S50,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"the investigators and sponsor were blinded to the lymphocyte count results and first-dose effects of ponesimod, unless alerted for safety reasons."
1517,PMC4215282,S51,['11b'],"[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,all ponesimod doses and matching placebo were indistinguishable and identically packaged.
1518,PMC4215282,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,the dose range selected for this study was based on phase i data.12 13
1519,PMC4215282,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"ponesimod 10 mg was selected as the lowest dose as it was associated with an approximate 50% reduction in peripheral lymphocyte counts,13 which was considered as the minimum reduction required for an immunomodulatory effect."
1520,PMC4215282,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,ponesimod 40 mg was selected as the highest dose as it was associated with an approximate 70% reduction in peripheral lymphocyte counts13; this degree of reduction has previously been shown to be associated with a significant therapeutic effect in patients with ms treated with fingolimod.18
1521,PMC4215282,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"furthermore, phase i studies demonstrated that through the use of an up-titration dosing regimen, the first-dose effects of ponesimod 20 and 40 mg on heart rate and conductivity were reduced, and the safety and tolerability of this higher dose were considered acceptable."
1522,PMC4215282,S56,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,study design is summarised in figure 1.
1523,PMC4215282,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,all patients randomised to ponesimod initially received ponesimod 10 mg (days 1–7).
1524,PMC4215282,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"on day 8, patients randomised to receive ponesimod 20 or 40 mg were up-titrated to the 20 mg dose and patients randomised to the 10 mg dose were mock up-titrated."
1525,PMC4215282,S59,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"on day 15, patients randomised to receive ponesimod 40 mg were up-titrated to the 40 mg dose; patients randomised to ponesimod 10 or 20 mg were mock up-titrated."
1526,PMC4215282,S60,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,patients randomised to placebo were mock up-titrated on days 8 and 15 (figure 1).
1527,PMC4215282,S61,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,figure 1 study design.
1528,PMC4215282,S62,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,all patients randomised to ponesimod initially received ponesimod 10 mg (days 1–7).
1529,PMC4215282,S63,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"on day 8, patients randomised to receive ponesimod 20 or 40 mg were up-titrated to the 20 mg dose and patients randomised to the 10 mg dose were mock up-titrated."
1530,PMC4215282,S64,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"on day 15, patients randomised to receive ponesimod 40 mg were up-titrated to the 40 mg dose; patients randomised to ponesimod 10 or 20 mg were mock up-titrated."
1531,PMC4215282,S65,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,patients randomised to placebo were mock up-titrated on days 8 and 15.
1532,PMC4215282,S66,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,patient numbers are for the all-treated population.
1533,PMC4215282,S67,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"fu, follow-up."
1534,PMC4215282,S68,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"study visits took place at screening, baseline, on day 1 (randomisation), days 8 and 15 (up-titration), at week 4 and then every 4 weeks until the end of the 24-week treatment period or study drug discontinuation."
1535,PMC4215282,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"patients who completed treatment at week 24 were offered enrolment into an ongoing, long-term, dose-blinded extension study where all patients would receive ponesimod (clinicaltrials.gov identifier: nct01093326)."
1536,PMC4215282,S70,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"for those patients who prematurely discontinued study treatment or who completed 24 weeks of treatment but chose not to enter the extension study, two safety follow-up visits were performed 7 and 30 days after the last dose of study drug (figure 1)."
1537,PMC4215282,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,"mri scans were performed at baseline, every 4 weeks from week 4 to 24 (end of treatment (eot)) and at the second safety follow-up visit for patients not entering the extension study."
1538,PMC4215282,S72,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,"mri scans were centrally evaluated in a fully blinded manner (medical image analysis centre, basel, switzerland)."
1539,PMC4215282,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,"edss assessments were performed at screening, baseline, week 24, at follow-up visit 2 and at unscheduled visits in case of ms relapse by an independent neurologist not otherwise involved in patient care."
1540,PMC4215282,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,"the main pharmacodynamic variable was total lymphocyte count, which was centrally analysed at screening, baseline, on days 8 and 15, every 4 weeks thereafter until eot and at the two safety follow-up visits."
1541,PMC4215282,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,"on treatment initiation and dose up-titration days, cardiac monitoring was performed by an independent cardiologist."
1542,PMC4215282,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,"this included 12-lead ecg, blood pressure measurements over 6 h and holter ecg monitoring over 24 h (subset of patients)."
1543,PMC4215282,S77,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and procedures,all ecg and holter measurements were centrally read in a blinded manner.
1544,PMC4215282,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,pulmonary function tests (pfts) were performed at all study visits except day 1 (randomisation).
1545,PMC4215282,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,unscheduled pfts were performed in the event of respiratory symptoms or decreased pft parameters during treatment.
1546,PMC4215282,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,adverse events (aes) and serious aes (saes) were collected at each visit.
1547,PMC4215282,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,laboratory assessments were performed at each visit except day 1 (randomisation).
1548,PMC4215282,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,aes of special interest were defined on the basis of preclinical and previous clinical safety findings for ponesimod.
1549,PMC4215282,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study design and procedures,"they were reported during the treatment and follow-up periods and grouped as follows: cardiovascular aes, infection-related aes, pulmonary aes, hepatobiliary disorders/liver toxicity and macular oedema."
1550,PMC4215282,S85,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,the primary efficacy endpoint was the cumulative number of new gd+ lesions per patient detected on t1-weighted mri scans from weeks 12 to 24.
1551,PMC4215282,S86,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,mri scans from weeks 4 and 8 were excluded from analysis of the primary endpoint due to the delayed anti-inflammatory effects evident with the s1p modulator fingolimod.18
1552,PMC4215282,S87,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,"in addition, the primary endpoint was aligned with that of another agent (dimethyl fumarate) with delayed onset of anti-inflammatory effects in patients with rrms.19"
1553,PMC4215282,S88,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,secondary efficacy endpoints were the annualised confirmed relapse rate (arr) and time to first confirmed relapse within 24 weeks of ponesimod initiation.
1554,PMC4215282,S89,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,"relapse was defined as the occurrence of an acute episode of one or more new symptoms or a worsening of existing symptoms of ms, not associated with fever or infection, and lasting for at least 24 h after a stable period of at least 30 days."
1555,PMC4215282,S90,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,"a confirmed relapse was defined as a relapse with an increase of ≥0.5 points from baseline in the edss score or an increase of one point in at least one functional system score (excluding bowel, bladder and mental functional systems) assessed within 7 days of onset by the independent neurologist."
1556,PMC4215282,S91,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study endpoints,"exploratory efficacy mri endpoints included cumulative number of new or enlarging non-enhancing t2 lesions at weeks 12, 16, 20 and 24; cumulative number of combined unique active lesions (cuals; sum of all new t1 gd+ lesions and new or enlarging t2 lesions since previous mri scan) at weeks 12, 16, 20 and 24; and percentage change from baseline to week 24 in brain volume as measured by mri using the structural image evaluation using normalisation of atrophy (siena) program.20"
1557,PMC4215282,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the global null hypothesis was that none of the three ponesimod groups differed from the placebo group in the mean cumulative number of new t1 gd+ lesions at weeks 12 to 24.
1558,PMC4215282,S94,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the alternate hypothesis was that at least one of the ponesimod treatment groups differed from the placebo group.
1559,PMC4215282,S95,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the test of the null hypothesis was based on a negative binomial regression model with treatment group as a four-level nominal covariate for the per-protocol analysis set.
1560,PMC4215282,S96,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the null hypothesis was tested by a wald χ2 test with a two-sided significance level of 5%.
1561,PMC4215282,S97,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,no adjustment was applied for multiple comparisons.
1562,PMC4215282,S98,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the per-protocol analysis set was defined as all randomised patients who received ≥80% of study drug from study drug initiation to the planned eot and had ≥2 valid post-baseline mris at weeks 12–24.
1563,PMC4215282,S99,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"the dose–response relationship was explored for the primary endpoint and lymphocyte counts by means of multiple comparison procedures and modelling techniques, as previously described.21"
1564,PMC4392313,S176,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,web supplement
1565,PMC4392313,S177,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,web table
1566,PMC4392313,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"this trial, conducted independently of the pivotal ra trials, was approved by an independent ethics committee or institutional review board, and all patients gave written informed consent for participation in the trial."
1567,PMC4392313,S47,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,adult patients with moderately to severely active ra (diagnosed per american college of rheumatology (acr) criteria) of more than 6 months’ duration were recruited.
1568,PMC4392313,S48,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"enrolment criteria included inadequate response to stable methotrexate (mtx) therapy, exemplified by a swollen joint count (sjc) ≥6 and a tender joint count (tjc) ≥6, together with c-reactive protein (crp) >10 mg/l or erythrocyte sedimentation rate (esr) >28 mm/h."
1569,PMC4392313,S49,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,patients with inadequate response to an antitumour necrosis factor-α (atnf) agent during the 6 months before baseline or to more than two previous atnf agents were ineligible.
1570,PMC4392313,S50,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,mtx therapy was continued during the study.
1571,PMC4392313,S51,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,"initiation of lipid-lowering, oral antidiabetic or antihypertensive medications or change in dose within 12 weeks of baseline was prohibited, and glucocorticoid doses (≤10 mg) had to remain stable."
1572,PMC4392313,S52,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Patients,"patients were stratified at randomisation by age (<52 vs ≥52 years), mean arterial blood pressure (<93.3 vs ≥93.3 mm hg) and crp (<1.66 vs ≥1.66 mg/dl)."
1573,PMC4392313,S54,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"this two-arm, randomised, multicentre, double-blind, placebo-controlled, parallel-group, phase iii study was conducted in the usa, canada and the uk (figure 1) at 34 sites (the measure study)."
1574,PMC4392313,S55,"['11a', '5', '8a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 1, 0, 0]",Procedures,"patients were randomly assigned using an interactive voice response system to blinded (patient and treating clinical team) intravenous treatment with tcz 8 mg/kg or placebo in a 1:1 ratio, both in combination with oral mtx, every 4 weeks for 6 months between november 2007 and june 2008."
1575,PMC4392313,S56,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"patients who, despite scheduled infusions of double-blind study medication at weeks 8 and 12, did not achieve ≥20% improvement from baseline in sjc and tjc at week 16 were offered escape therapy with open-label tcz 8 mg/kg."
1576,PMC4392313,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"at completion of the 24-week randomised treatment period, all patients were offered open-label treatment with tcz 8 mg/kg plus mtx."
1577,PMC4392313,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"assessments during part 1 (randomised phase) of the study were performed at day 1 and at weeks 1, 2, 4, 8, 12, 16, 20 and 24."
1578,PMC4392313,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,open-label assessments were performed every 12 weeks to week 104 (clinicaltrials.gov number nct00535782).
1579,PMC4392313,S60,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"the study protocol (version c, 22 june 2009 (original protocol published 10 may 2007)) is available as online supplementary material."
1580,PMC4392313,S61,"['3a', '5']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,figure 1 study design.
1581,PMC4392313,S62,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"mtx, methotrexate; tcz, tocilizumab."
1582,PMC4392313,S63,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,(a) *patients who did not achieve ≥20% improvement from baseline in swollen and tender joint counts at week 16 were offered escape therapy with open-label tcz 8 mg/kg.
1583,PMC4392313,S64,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,†60 placebo+mtx and 65 tcz+mtx patients completed 12 weeks.
1584,PMC4392313,S65,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,‡59 placebo+mtx and 65 tcz+mtx patients completed 24 weeks.
1585,PMC4392313,S66,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,(b) *tcz 8 mg/kg every 4 weeks+background mtx (7.5–25 mg weekly).
1586,PMC4392313,S67,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"†escape therapy, open-label tcz (8 mg/kg every 4 weeks+background mtx)."
1587,PMC4392313,S68,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,‡patients who received at least one dose of tcz (double-blind or open-label).
1588,PMC4392313,S70,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Lipid and biomarker assays,"commercial assays were used to measure cholesterol, triglycerides, apolipoproteins a1 and b (apoa1 and apob), crp (by high-sensitivity assay) and esr (all assays conducted or facilitated by covance laboratories, greenfield, indiana, usa)."
1589,PMC4392313,S71,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Lipid and biomarker assays,"serum lipid subclasses were characterised by nuclear magnetic resonance (nmr; liposcience, raleigh, north carolina, usa)."
1590,PMC4392313,S72,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Lipid and biomarker assays,"assays for hdl-associated saa and serum paraoxonase, secretory phospholipase a2-iia (spla2-iia), oxidised ldl, d-dimer, fibrinogen, lp(a) and haptoglobin were performed at pacific biomarkers, inc. (seattle, washington, usa)."
1591,PMC4392313,S73,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Lipid and biomarker assays,specific details are provided as online supplementary material.
1592,PMC4392313,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Vascular physiology,"arterial stiffness was assessed by pwv according to the manufacturer's instructions using a pulse wave analysis apparatus (sphygmocor; atcor, san jose, california, usa).19"
1593,PMC4392313,S76,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Vascular physiology,"blinded assessors from all centres underwent training with an expert assessor, and certification was provided by atcor."
1594,PMC4392313,S77,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Vascular physiology,"all pwv scans were reviewed by atcor, and only those meeting predetermined quality control measures were accepted for analysis (details in online supplementary material)."
1595,PMC4392313,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,the primary objective was to investigate the effect of 12 weeks of treatment with tcz on pwv and on small ldl particle number assessed by nmr compared with placebo.
1596,PMC4392313,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,the secondary objective was to investigate the effect of tcz compared with placebo on these measurements at week 24.
1597,PMC4392313,S81,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all other analyses, including lipid and lipoprotein parameters, were exploratory."
1598,PMC4392313,S82,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"a sample size of 120 patients (60 per arm), calculated based on previous results in patients with ra,5 18 was expected to provide sufficient power to detect a difference at week 12 in pwv (−1.14 m/s) and small ldl (−5.51 mg/dl (30% reduction)) in patients treated with tcz compared with placebo."
1599,PMC4392313,S83,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the co-primary efficacy end points of change from baseline in pwv and small ldl particle number were analysed by parametric analysis of covariance.
1600,PMC4392313,S84,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the 12-week and 24-week efficacy analyses of primary and secondary end points were performed on the intent-to-treat (itt) population using last-observation-carried-forward to impute missing data at the analysis time point.
1601,PMC4392313,S85,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,only measurements recorded before escape therapy were carried forward.
1602,PMC4392313,S86,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all other exploratory end points were summarised for the itt population observed cases, without imputation of missing data and excluding escape data."
1603,PMC4392313,S87,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all laboratory parameter values were converted to si units; for lipid parameters, only the latest fasted values within the time window were included."
1604,PMC4392313,S88,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"assumptions of normality and homogeneity of the variance were assessed by inspecting normal probability plots, plots of standardised residual versus predicted values and plots of standardised residual versus continuous covariates."
1605,PMC4392313,S89,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"primary end points in the study were analysed based on a normal distribution; however, because baseline values for several laboratory assessments in this study demonstrated non-normal distributions, values for exploratory serum analytes are presented as medians or median percentage changes from baseline."
1606,PMC4392313,S90,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"exploratory analyses, based on observed cases, were performed using the non-parametric kruskal–wallis test."
1607,PMC4392313,S91,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,hodges–lehmann estimates of location shift and 95% cis are presented.
1608,PMC4392313,S92,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,no adjustments for multiplicity were performed.
1609,PMC4431679,S40,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"this was an open label, parallel, one to one randomised controlled trial, conducted in four acute care hospitals (rabin medical center, petah-tikva (192 patients); rambam health care campus (38 patients); holy family hospital nazareth (7 patients); wolfson medical center (6 patients)) in israel, between july 2007 and april 2014."
1610,PMC4431679,S41,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,informed consent was obtained from all patients or their legal guardian.
1611,PMC4431679,S43,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,"we included adult inpatients with severe infections caused by mrsa, including bacteraemia, and patients with highly probable mrsa infections."
1612,PMC4431679,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,"we defined bacteraemia as the isolation of mrsa in more than one blood culture bottle or isolated in a single bottle and accompanied by fever above 38°c, chills, or systolic blood pressure under 90 mm hg."
1613,PMC4431679,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,"we defined other microbiologically documented mrsa infections by using predefined criteria adapted from surveillance definitions of healthcare associated infections,26 plus isolation of mrsa from a sterile sample from the source of infection."
1614,PMC4431679,S46,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,patients with skin and soft tissue infections could be included only if they fulfilled the sepsis inflammatory response syndrome criteria.27
1615,PMC4431679,S47,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,"patients with polymicrobial infections could be included, except those involving meticillin susceptible s aureus or mandating treatment with vancomycin or trimethoprim-sulfamethoxazole."
1616,PMC4431679,S48,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,"the highly probable group included patients with ventilator associated pneumonia and prior antibiotic treatment, central catheter related infections, and surgical site infections in the presence of a foreign body, all without microbiological documentation.28"
1617,PMC4431679,S49,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,"we excluded patients who had received trimethoprim-sulfamethoxazole or vancomycin for more than 48 hours; patients with mrsa resistant to trimethoprim-sulfamethoxazole or vancomycin; those with highly suspected or confirmed left sided endocarditis or meningitis; patients with chronic renal failure (creatinine clearance <15 ml/min) and chronic haemodialysis (those with severe acute renal failure, including acute haemodialysis, could be included); neutropenic patients with acute leukaemia or bone marrow transplantation; and patients with known allergy to either study drug, treatment with methotrexate, pregnancy or lactation, previous enrolment in this study, or concurrent participation in another trial."
1618,PMC4431679,S50,['8a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Study population and procedures,we used a central computer generated random number list to randomise patients to treatment with trimethoprim-sulfamethoxazole or vancomycin.
1619,PMC4431679,S51,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Study population and procedures,"allocation was concealed in sealed, opaque numbered envelopes that were opened consecutively after informed consent was obtained."
1620,PMC4431679,S52,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,trimethoprim-sulfamethoxazole was started intravenously at a dose of 320 mg trimethoprim/1600 mg sulfamethoxazole twice daily and could be switched to oral treatment using the same dose at the discretion of the treating physician.
1621,PMC4431679,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,dosing was based on a pharmacokinetic study showing that a lower dose resulted in inhibition but not killing of s aureus and on the dose used in a previous trial.23 29
1622,PMC4431679,S54,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,the vancomycin starting dose was 1 g twice daily.
1623,PMC4431679,S55,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,"in both arms, treatment was adjusted to renal function; in the vancomycin arm, it was directed by serum concentrations to obtain drug trough concentrations between 10 and 20 mg/dl."
1624,PMC4431679,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,the complete study protocol is available on request.
1625,PMC4431679,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,"treatment had to be administered for a minimum of seven days, following which the duration depended on the indication."
1626,PMC4431679,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,"concomitant antibiotics, other than the combination of vancomycin and co-trimoxazole, could be administered."
1627,PMC4431679,S59,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and procedures,"after randomisation, no blinding was performed, but outcomes were adjudicated blinded to allocation."
1628,PMC4431679,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"the primary efficacy outcome was clinical treatment failure at seven days and was a composite of death, persistence of fever (<38°c for two consecutive days and no increase above 38° after resolution was required to rule out persistence), persistence of hypotension (<90 mm hg systolic or need for vasopressor support), non-improving sequential organ failure assessment (sofa) score (for baseline sofa ≥3, a decrease of at least 30% was required; and for baseline sofa <3, a stable or decreased sofa score was required to rule out failure), or persistent bacteraemia on day 7."
1629,PMC4431679,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"blood cultures were repeated on day 2 for all patients with bacteraemia and daily thereafter for patients with persistent fever, persistent bacteraemia, or other signs of infection."
1630,PMC4431679,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,we also defined a primary safety outcome of all cause mortality at 30 days.
1631,PMC4431679,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"secondary outcomes included failure or modification of treatment, comprising treatment failure (as defined) or antibiotic treatment modification; bacteriological failure, defined as growth of mrsa on day 7 cultures; persistence of bacteraemia at 48 hours; length of hospital admission; duration of fever, summing all days with at least one measurement of temperature 38°c or above until day 30; and development of resistance defined as acquisition of trimethoprim-sulfamethoxazole or vancomycin resistant s aureus or vancomycin resistant enterococci."
1632,PMC4431679,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"adverse events included renal failure defined using rifle criteria,30 rash, leucopoenia, any diarrhoea and clostridium difficile associated diarrhoea, and other adverse events."
1633,PMC4431679,S67,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size and analysis,"to establish non-inferiority, we allowed a difference of up to 15% in the primary outcome."
1634,PMC4431679,S68,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size and analysis,"assuming a 30% treatment failure rate for both treatment groups, we needed a sample of 128 patients per arm for a one sided test to rule out the pre-specified difference in the 95% confidence interval of the difference between groups, allowing for 10% non-evaluable patients (α=0.05, β=0.8)."
1635,PMC4431679,S69,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Sample size and analysis,"we did interim analyses of the primary safety outcome after recruitment of one third and two thirds of patients, with stopping boundaries (two sided α level, p<0.01)."
1636,PMC4431679,S70,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and analysis,we did the primary analysis by intention to treat.
1637,PMC4431679,S71,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and analysis,we did per protocol analysis for patients without exclusion criteria after randomisation who received allocated treatment for a minimum of seven days.
1638,PMC4431679,S72,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and analysis,we did subgroup analysis for patients with mrsa bacteraemia.
1639,PMC4431679,S73,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and analysis,we used χ2 or fisher’s exact tests to compare categorical outcomes.
1640,PMC4431679,S74,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and analysis,"continuous outcomes were skewed, so we described them as medians and compared them by using a median difference, all with 95% confidence intervals.31"
1641,PMC4431679,S75,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and analysis,"we did multivariable analyses for the primary efficacy outcome, including the treatment arm as an independent variable."
1642,PMC4431679,S76,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and analysis,we entered all variables significantly associated with the outcome on univariate analysis (p<0.05) and not correlated (spearman correlation >0.5) into a logistic regression analysis.
1643,PMC4431679,S77,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and analysis,we present risk ratios or odds ratios with 95% confidence intervals.
1644,PMC4469977,S100,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"we chose a difference of 0.5 standard deviations as being a clinically meaningful between group difference, as observational data suggested that ciclosporin was potentially more effective, but at higher cost, than prednisolone.19 20 21"
1645,PMC4469977,S101,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"as a result, we felt that a substantial treatment effect was necessary to justify a change in clinical practice."
1646,PMC4469977,S103,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we prespecified all analyses in a statistical analysis plan.
1647,PMC4469977,S104,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"analysis was conducted using intention to treat principles; defined as all randomised participants, excluding those with a later diagnosis determined to be something other than pyoderma gangrenosum."
1648,PMC4469977,S105,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we included all participants with available data at both the baseline and the six week visit in the primary analysis.
1649,PMC4469977,S106,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the impact of missing values was explored in sensitivity analysis.
1650,PMC4469977,S107,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"a linear regression model was used to analyse differences between treatment groups for the primary outcome at six weeks, adjusting for the stratification variables."
1651,PMC4469977,S108,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"secondary outcomes were analysed using cox regression models (for time to event outcomes); linear regression models for dermatology life quality index, eq-5d, and eq-vas (adjusted for baseline values), and for self reported pain (which were summarised using area under the curve); proportional odds models for ordered categorical outcomes; and logistic regression models for binary outcomes."
1652,PMC4469977,S109,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,all analyses were adjusted for the stratification variables.
1653,PMC4469977,S110,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"sensitivity analysis of the primary outcome and time to healing were further adjusted for additional baseline variables including age, sex, weight, size of recruiting centre and geographical region; missing data; and participants who switched randomised treatments or received the trial drugs in combination during the period of the trial."
1654,PMC4469977,S111,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we analysed adverse reactions that occurred during the trial according to the original randomised allocation, regardless of whether other drugs had been introduced before the adverse reaction."
1655,PMC4469977,S112,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all statistical analyses were conducted using sas software, version 9.2 and r version 2.10.1."
1656,PMC4469977,S39,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,the trial protocol has been published previously.11
1657,PMC4469977,S41,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and oversight,"we carried out a multicentre, parallel group, observer blind randomised controlled trial to compare the efficacy and safety of ciclosporin with that of prednisolone."
1658,PMC4469977,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and oversight,participants gave written informed consent.
1659,PMC4469977,S43,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and oversight,oversight of the trial included a trial management group and independent trial steering and data monitoring committees.
1660,PMC4469977,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design and oversight,"patients suitable for topical treatment were entered into a parallel observational study, the results of which will be reported separately."
1661,PMC4469977,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient involvement,patients were involved in the design and conduct of this research.
1662,PMC4469977,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient involvement,"during the feasibility stage, priority of the research question, choice of outcome measures, and methods of recruitment were informed by discussions with patients through a focus group session and two structured interviews."
1663,PMC4469977,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient involvement,"during the trial, a patient joined the independent trial steering committee."
1664,PMC4469977,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient involvement,members of the uk dermatology clinical trials network also identified this research as being a priority area for clinicians treating patients with pyoderma gangrenosum.
1665,PMC4469977,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient involvement,"once the trial has been published, participants will be informed of the results through a dedicated website (www.stopgaptrial.co.uk) and will be sent details of the results in a study newsletter suitable for a non-specialist audience."
1666,PMC4469977,S52,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,recruitment took place at 39 hospitals in the united kingdom.
1667,PMC4469977,S53,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"participants were aged 18 years or more, with a diagnosis of pyoderma gangrenosum made by a recruiting dermatologist."
1668,PMC4469977,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"histopathology is rarely pathognomonic for pyoderma gangrenosum, and many clinicians avoid biopsy because of the risk of an immunological reaction that results in ulcer extension at the biopsy site."
1669,PMC4469977,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"if the clinical diagnosis was uncertain, a biopsy was performed to exclude other diagnoses such as malignancy, granulomatous pyoderma gangrenosum, and arteritis, and advice was sought from an expert panel as necessary."
1670,PMC4469977,S56,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"we excluded patients with pustular or granulomatous variants of pyoderma gangrenosum (as they may respond differently to treatment, and measurement of a single ulcer was not possible); patients receiving oral prednisolone, ciclosporin, or intravenous immunoglobulin in the previous month; patients participating in another clinical trial; women who were pregnant, lactating, or at risk of pregnancy; patients with known hypersensitivity to either of the study treatments; patients with clinically important renal impairment or other pretreatment findings that would result in the investigator not using either of the study drugs; patients with malignant or premalignant disease; patients with a concurrent medical condition for which treatments might interfere with ongoing treatment or cause harm; and patients taking rosuvastatin or those who had received a live vaccine in the two weeks before randomisation."
1671,PMC4469977,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Interventions,participants received oral prednisolone (brand chosen according to local practice) 0.75 mg/kg/day in a single dose or ciclosporin (neoral; novartis) 4 mg/kg/day in two divided doses.
1672,PMC4469977,S59,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Interventions,"as this was a pragmatic trial, the dose could be adjusted according to normal practice, to a maximum of 1 mg/kg/day for prednisolone and 5 mg/kg/day for ciclosporin.7 10"
1673,PMC4469977,S60,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Interventions,topical treatment was prohibited during the trial.
1674,PMC4469977,S61,['3b'],"[0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Interventions,a change to the protocol was made in august 2011 (after 82 participants had been enrolled) as bowel perforation was experienced by a participant receiving prednisolone 110 mg/day.
1675,PMC4469977,S62,['3b'],"[0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Interventions,as a result we implemented ceiling doses of 75 mg/day for prednisolone and 400 mg/day for ciclosporin.
1676,PMC4469977,S64,"['8a', '8b', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Randomisation and blinding,"participants were randomised (1:1) to treatment allocation using a web based randomisation system hosted by nottingham clinical trials unit, using a computer generated pseudorandom list, with permuted blocks of randomly varying size between two and six (ralloc add-on12 for stata, tx)."
1677,PMC4469977,S65,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Randomisation and blinding,randomisation was stratified by target lesion size (<20 cm2; ≥20 cm2) and presence or absence of underlying systemic disease.
1678,PMC4469977,S66,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and blinding,it was not possible to blind clinicians and participants to treatment allocation owing to resource limitations and the complexities of different dosing regimens and safety testing of the two drugs.
1679,PMC4469977,S67,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and blinding,"as a result, clinicians and participants were informed of their treatment allocation once data had been irrevocably entered into the randomisation database."
1680,PMC4469977,S68,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and blinding,"treatment allocation was concealed from the statistician and blinded assessors of the digital images until interventions were all assigned and recruitment, data collection, data cleaning, and blind analysis were complete."
1681,PMC4469977,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and blinding,assessors blind to the allocated treatment assessed the ulcer size and global treatment response from digital images of the target lesion.
1682,PMC4469977,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and blinding,"if digital images were not available, the assessors used physical measurements of the lesion taken during clinic visits and global response by the treating clinician."
1683,PMC4469977,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"clinic visits took place at baseline, week 2, and week 6 (primary outcome) and when the ulcer had healed (up to a maximum of six months)."
1684,PMC4469977,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,patient reported outcomes were collected from daily diaries or postal questionnaires.
1685,PMC4469977,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"for participants whose pyoderma gangrenosum had healed, we assessed recurrence and time to recurrence from medical notes."
1686,PMC4469977,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Digital image assessments,a template was photographed alongside the target ulcer to calibrate the image in the image analysis software (see supplementary figure).
1687,PMC4469977,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Digital image assessments,"two trained assessors mapped the circumference of the lesion using verg videometry vev md software (vista medical, winnipeg, canada)."
1688,PMC4469977,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Digital image assessments,two dermatologists independently reviewed all images to ensure that the lesions were consistent with a diagnosis of pyoderma gangrenosum and that the measurements taken by the trained assessors were an accurate representation of the ulcer’s size.
1689,PMC4469977,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"the main outcome measure was speed of healing over six weeks, captured for a single target lesion for each patient."
1690,PMC4469977,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"if multiple lesions were present, we designated the largest lesion that could be photographed on a single plane as the target lesion."
1691,PMC4469977,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"we chose speed of healing for the primary outcome as previous studies have shown it to be a good predictor of healing in patients with leg ulcers,13 14 and because blinded outcome assessment was possible using digital images and independent assessors."
1692,PMC4469977,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,assessing the primary outcome at six weeks also minimised loss to follow-up and the impact of participants switching to alternative treatments before primary outcome assessment.
1693,PMC4469977,S85,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"in cases where digital images were unavailable, or of poor quality, we used physical measurements of the ulcer taken by non-blinded clinicians at baseline and six weeks."
1694,PMC4469977,S87,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Secondary outcomes,time to healing—defined as the time at which sterile dressings were no longer required (reported by patients and confirmed by clinicians at subsequent clinic visits).
1695,PMC4469977,S88,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Secondary outcomes,we identified this outcome as the most important of the secondary outcomes.
1696,PMC4469977,S89,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Secondary outcomes,pyoderma gangrenosum specific global treatment response—to assess treatment response we used a seven point likert scale ranging from completely clear through to worse (assessed by clinicians and participants and from digital images for blinded assessment).
1697,PMC4469977,S90,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Secondary outcomes,resolution of inflammation—this was recorded by clinicians and participants using a scale reported by foss.15
1698,PMC4469977,S91,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Secondary outcomes,"self reported pain—participants self reported the severity of pain daily using a score from 0 to 4 (none, mild, moderate, severe, or extreme)."
1699,PMC4469977,S92,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Secondary outcomes,"health related quality of life—assessed using the dermatology life quality index16 and european quality of life-5 dimensions, three levels (eq-5d-3l and eq vas).17 18"
1700,PMC4469977,S93,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Secondary outcomes,time to recurrence—defined as the interval between the target lesion healing and a further episode of pyoderma gangrenosum (at any site).
1701,PMC4469977,S94,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Secondary outcomes,the period of follow-up available varied depending on the time at which participants were randomised into the trial.
1702,PMC4469977,S95,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Secondary outcomes,"number of treatment failures—defined as those who withdrew from their randomised treatment because of treatment intolerance, whose pyoderma gangrenosum worsened, or whose target lesion remained unhealed after six months of follow-up."
1703,PMC4469977,S96,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Secondary outcomes,"adverse reactions to study drugs—adverse events that were possibly, probably, or definitely related to the study drug."
1704,PMC4469977,S98,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size,"this was a superiority trial, with prednisolone as the control intervention."
1705,PMC4469977,S99,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"to provide 80% power (5% level of significance) to detect a difference in means of 0.5 standard deviations in the primary outcome of speed of healing over six weeks, the target sample size was 140 participants, assuming a loss to follow-up of 10%."
1706,PMC4515982,S100,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the kaplan-meier method was used to obtain survival curves with the corresponding log-rank test.
1707,PMC4515982,S101,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"a cox model was applied to estimate the treatment effect in terms of hr with 95% ci, adjusted for sex, age, alsfrs-r score at baseline and disease duration."
1708,PMC4515982,S102,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the number of patients experiencing an ae causing withdrawal were reported and compared between the two groups by kaplan-meier curves of the time to withdrawal and the corresponding log-rank test.
1709,PMC4515982,S103,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"change from baseline in svc, alsfrs-r and alsaq-40 was assayed by mixed effect models."
1710,PMC4515982,S104,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all data were analysed using sas v.9.3 (sas institute inc. cary, north carolina, usa)."
1711,PMC4515982,S105,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"this study is registered with eudract, number 2009-016066-91 (epos trial)."
1712,PMC4515982,S40,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,the trial was coordinated by the als centre at the irccs foundation ‘carlo besta’ of milan.
1713,PMC4515982,S41,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,consecutive patients were screened for eligibility at all the 25 italian als centres.
1714,PMC4515982,S42,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients aged 18–75 years and diagnosed with probable laboratory-supported, probable or definite als according to el escorial revised criteria were eligible."
1715,PMC4515982,S43,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,inclusion criteria were onset of weakness ≤18 months and slow vital capacity (svc) ≥70% of predicted in seated position at screening visit.
1716,PMC4515982,S44,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"exclusion criteria were haematocrit >51% in men and >49% in women, haemoglobin value >17 g/dl; non-invasive ventilation (niv) >6 h daily; known familial als or first-degree relative with als; diagnosis of frontotemporal dementia; history and/or instrumental evidence of previous thrombotic vascular event or cardiac diseases; uncontrolled hypertension (systolic ≥160 mm hg and diastolic ≥95 mm hg irrespective of treatments at two consecutive evaluations); active solid or myeloproliferative malignancy; known hypercoagulable disorders."
1717,PMC4515982,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,all patients were asked to continue riluzole 100 mg daily or to be on a stable dose for at least 30 days prior to screening.
1718,PMC4515982,S46,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients who did not take riluzole at the screening visit were considered eligible and could be randomized; in this case, they could not start riluzole during the entire study period."
1719,PMC4515982,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,the protocol was approved by the ethics committee at each site.
1720,PMC4515982,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,all patients provided written informed consent before any study-related procedure.
1721,PMC4515982,S50,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Trial outcomes,"the primary outcome was one single composite outcome of time from randomisation to death, tracheotomy or >23 h niv daily for 14 consecutive days."
1722,PMC4515982,S51,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Trial outcomes,"secondary outcomes were changed from baseline in the alsfrs-r score, svc in the seated position and patients’ quality of life measured by the alsaq-40 questionnaire."
1723,PMC4515982,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Trial outcomes,tolerability was evaluated analysing adverse events (aes) causing withdrawal.
1724,PMC4515982,S54,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Randomisation,patients were randomly assigned to receive either intravenous rhepo 40 000 iu or matching placebo (1:1 ratio) fortnightly for 12 months.
1725,PMC4515982,S55,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Randomisation,"randomisation was stratified by centre, disease severity (alsfrs-r ≤33 vs >33) and onset (spinal or bulbar), with a block size of four within each centre."
1726,PMC4515982,S56,"['8a', '9', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 1]",Randomisation,"the neuroepidemiology unit at the coordinating centre, independent of the study, generated the computer-based randomisation sequence known only to two staff persons and the drug dispenser."
1727,PMC4515982,S57,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,"treatment was allocated by a web-based randomisation system, available 24 h a day."
1728,PMC4515982,S58,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,the procedure incorporated eligibility checks according to protocol and was performed on request from the centres.
1729,PMC4515982,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation,the sequence was always available for emergency unmasking.
1730,PMC4515982,S61,['11b'],"[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Masking,"rhepo (eprex) was purchased from janssen-cilag spa (cologno monzese, italy) by the coordinating centre and directly shipped to the company (pierrel research imp srl, cantù, italy) in charge of preparing the investigational drug (rhepo or 1 cc of saline) in syringes of identical appearance, sealed in sequentially numbered identical containers according to the allocation sequence."
1731,PMC4515982,S62,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Masking,shipping was performed for each patient within 1 week after randomisation using a refrigerated express carrier.
1732,PMC4515982,S63,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Masking,each centre stored the investigational drug at −4°c.
1733,PMC4515982,S64,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Masking,"patients, neurologists, laboratory biologists/technicians (two at each centre) and a statistician were masked to treatment allocation and did not have access to any data related to rhepo haematopoietic activity."
1734,PMC4515982,S65,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Masking,"briefly, all participating centres generated a specific access code for the blood withdrawals of patients with als enrolled in the epos trial."
1735,PMC4515982,S66,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Masking,"at each treatment visit, the local laboratory unit received the de-identified vial reporting the randomisation number before treatment administration."
1736,PMC4515982,S67,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Masking,blood parameters were emailed to the coordinating unit where a trained person readily alerted the treating neurologist on the decision to administer or delay the treatment based on safety protocol parameters (see below).
1737,PMC4515982,S68,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Masking,"patients and treating neurologists did not have access to any data on blood parameters, whereas laboratory personnel did not have access to any data allowing the identification of the patient."
1738,PMC4515982,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Masking,this procedure was elaborated to maintain the blindness of the study.
1739,PMC4515982,S70,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Masking,"finally, when we designed the study, we reasoned that patients treated with rhepo could have had a higher risk of treatment delay as defined by the safety protocol."
1740,PMC4515982,S71,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Masking,"therefore, the randomisation centre generated a list of placebo patients randomly assigned to 1 week treatment delay balanced with the number of patients allocated on rhepo treatment needing true delay at each centre."
1741,PMC4515982,S72,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Masking,this procedure was elaborated to maintain the blindness of the study.
1742,PMC4515982,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"after giving informed written consent, eligible patients underwent haematological examinations (haemochromocytometry, renal and liver function, serum iron, ferritin, transferrin, reticulocyte count, coagulation tests), blood pressure and body mass index (bmi) measurement and svc, alsfr-r and alsq40 assessment."
1743,PMC4515982,S75,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,randomisation was performed within 15 days after the screening visit.
1744,PMC4515982,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"at each fortnightly treatment visit, safety parameters (haematocrit >51% in men and >49% in women or haemoglobin value >17 g/dl and value raised >1 g/dl at the end of the interval between two subsequent doses), blood pressure and bmi were assessed."
1745,PMC4515982,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"symptoms of nocturnal hypoventilation (nocturnal arousals, morning headache, excessive daytime sleepiness, vivid dreams), medications and ae were actively monitored and recorded."
1746,PMC4515982,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,alsfr-r and svc were assessed monthly.
1747,PMC4515982,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"at the 6-month and study end or dropout visit, the patient also underwent complete haematological examinations and alsaq-40 assessment."
1748,PMC4515982,S80,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"at each treatment visit, treatment administration was allowed or delayed for 1 week by the trial coordinating office after assessment of safety parameters."
1749,PMC4515982,S81,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"if treatment was delayed, the following week safety parameters were repeated before drug administration."
1750,PMC4515982,S82,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,the delay of treatment administration for more than two times caused the dropout of the patient.
1751,PMC4515982,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"after the study end at month 12, patients underwent monthly follow-up visits for a further 6 months to record primary outcome events."
1752,PMC4515982,S84,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"all centres were provided with a spirometer (spirobank g multifunction, medisan srl, milano, italy) and disposable tubes for svc assessment, and trained in its use."
1753,PMC4515982,S85,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"all data were recorded by an electronic case record form specifically developed (nubilaria srl, novara, italy)."
1754,PMC4515982,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"trial monitoring was performed by an independent contract research organisation (crom srl, verona, italy) that assured consistency in measuring outcomes across centres by scheduled site visits."
1755,PMC4515982,S88,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Co-treatments,nutritional status and ventilation could affect survival and thus the primary outcome of the trial.
1756,PMC4515982,S89,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Co-treatments,"during the first investigator meeting held in milan on 6 june 2010, all participating centres agreed on the approach to cotreatments, sharing the opinion that the ultimate decision would be personal to each patient."
1757,PMC4515982,S90,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Co-treatments,"we agreed that percutaneous endoscopic gastrostomy or an equivalent device should be proposed to all patients in the case of score 1 or 2 at item 3 of the alsfrs-r, unintentional loss of body weight >10% in the past 3 months or choking during food, liquids or medication ingestion."
1758,PMC4515982,S91,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Co-treatments,"niv should be proposed to all patients in the case of score 0 or 1 at item 10 or 11 of the alsfrs-r, svc<50% or abnormal nocturnal oximetry (sao2 <90% for 4% of the overnight recorded time)."
1759,PMC4515982,S93,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size estimation,"on the basis of the results of our pilot study (ie, observed rates of 0.56 for death and 0.33 for tracheotomy at 18 months in the placebo group),13 we estimated that we would need a sample size of 203 patients followed up for 12 months to give 97% power to detect a significant difference between rhepo and placebo corresponding to a 67% relative reduction of risk of death and 74% power to detect a 70% relative reduction of risk of respiratory events (tracheotomy or >23 h niv), with a two-sided type 1 error of 5% and given an anticipated dropout rate of 10%."
1760,PMC4515982,S95,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the main analysis of primary and secondary outcomes included all randomised patients who took at least one dose of the investigational drug in their original assigned groups.
1761,PMC4515982,S96,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,all analyses were performed both for the entire population and for the subgroups of patients with alsfrs-r ≥33 or <3314 and with spinal or bulbar onset at randomisation.
1762,PMC4515982,S97,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,a per-protocol analysis was carried out excluding non-compliers (patients who took <80% therapy).
1763,PMC4515982,S98,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"demographic characteristics and clinical features of randomised patients at baseline were reported by treatment arm and compared using χ2 test, student t test, wilcoxon rank-sum test or fisher’s exact test as appropriate."
1764,PMC4515982,S99,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"time from randomisation to death, tracheotomy or >23 h niv daily for 14 consecutive days was analysed in terms of the annualised rate with the corresponding 95% ci, and p value using a χ2 test with one degree of freedom for rate comparison (based on poisson regression)."
1765,PMC4621368,S39,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Trial population,"between june 2011 and september 2013, consecutive patients referred for elective cabg surgery were recruited from two clinics at edinburgh heart centre."
1766,PMC4621368,S40,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial population,"patients were 18 years or older, and were referred for isolated cabg surgery requiring two or more grafts."
1767,PMC4621368,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial population,"exclusion criteria included patients with recent myocardial infarction (within 1 month of surgery), emergency or concomitant valve surgery, significant renal impairment (estimated glomerular filtration rate<40 ml/min), severe respiratory disease (maintenance corticosteroid therapy or forced expiratory volume in 1 s <50% predicted), severe lv impairment (ef <40%), contraindication to magnetic resonance scanning, treatment for chronic inflammatory disease, women of childbearing potential and inability to provide consent."
1768,PMC4621368,S43,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study drug and randomisation,"intravenous recombinant human elafin (proteo biotech ag, germany) 200 mg or saline placebo was prepared and infused as aqueous solution of 250 ml 0.9% saline."
1769,PMC4621368,S44,"['8b', '10', '9']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1]",Study drug and randomisation,patients were randomised (1:1) to receive elafin or matched placebo by edinburgh clinical trials unit to ensure allocation concealment.
1770,PMC4621368,S45,"['11a', '8b']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Study drug and randomisation,"randomisation incorporated minimisation for age, presence of diabetes mellitus, extent of coronary artery disease, renal function and surgeon a or b. to ensure blinding, study drugs were prepared by staff independent of the study investigators or clinical team responsible for the patient’s care."
1771,PMC4621368,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study drug and randomisation,intravenous elafin 200 mg causes complete inhibition of plasma elastase activity for 2 h and >50% inhibition for 6 h.
1772,PMC4621368,S47,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study drug and randomisation,this dosage regimen was selected to cover the increased elastase release following cabg surgery that peaks at the time of weaning from cardiopulmonary bypass and has returned to baseline by 6–7 h.
1773,PMC4621368,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study drug and randomisation,the study drug was administered to the patient through a central venous cannula over a period of 30 min. the intravenous infusion was started at first skin incision and completed at least 20 min before cardiopulmonary bypass commenced.
1774,PMC4621368,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Anaesthesia and coronary artery bypass surgery,general anaesthesia was maintained with isoflurane and propofol infusion during bypass.
1775,PMC4621368,S51,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Anaesthesia and coronary artery bypass surgery,surgical approach was via a median sternotomy and cardiopulmonary bypass was started after heparin administration with a non-pulsatile flow and a membrane oxygenator.
1776,PMC4621368,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Anaesthesia and coronary artery bypass surgery,"cardioprotection was provided by cold blood cardioplegia (1:4), which was administered antegradely, after cross-clamping the aorta, into the coronary arteries or by cross-clamp fibrillation."
1777,PMC4621368,S54,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Blood samples,"blood samples were taken at baseline (time 0, skin incision) and at 2, 6, 24 and 48 h postoperatively."
1778,PMC4621368,S55,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Blood samples,"plasma cardiac troponin i (ctni) concentrations were measured with the architectstat troponin i assay and architectstat high-sensitive troponin i assay (abbott laboratories, abbott park, illinois, usa) validated in our institution.16 17"
1779,PMC4621368,S56,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Blood samples,"plasma concentrations of high-sensitive c reactive protein, il-6, il-8, myeloperoxidase and elastase were quantified using elisas (r&d systems, uk; elastase elisa, cambridge biosciences, uk)."
1780,PMC4621368,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Blood samples,"plasma elastase activity and serum elafin concentrations were measured by the department of dermatology, university of kiel, germany."
1781,PMC4621368,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Cardiac MRI and analysis,each patient underwent cardiac mri twice: within 6 weeks before surgery and from 5 days after surgery.
1782,PMC4621368,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Cardiac MRI and analysis,"patients were scanned using a research-dedicated 3t siemens verio scanner (siemens medical, germany)."
1783,PMC4621368,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Cardiac MRI and analysis,"quantification of lv mass, ef and late gadolinium enhancement infarct size were determined using established protocols and dedicated cardiac analysis software by two trained independent blinded observers."
1784,PMC4621368,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,the primary outcome variable was the 48 h area under the curve (auc) for plasma ctni concentration.
1785,PMC4621368,S64,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"it was analysed using a generalised linear model, including terms for the treatment allocation and the variables on which the randomisation was minimised."
1786,PMC4621368,S65,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"log transformations were applied as the data were skewed, and the results have been unlogged and presented as geometric means."
1787,PMC4621368,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"secondary outcome measures involving the auc (hs-crp, il-6, il-8, myeloperoxidase and elastase) were analysed similarly, taking log transformation if the data were skewed."
1788,PMC4621368,S67,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"lvef and mass were analysed using qmass software (medis medical imaging systems, the netherlands)."
1789,PMC4621368,S68,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"the change in volume of infarction from preoperative and first postoperative magnetic resonance scans was categorised as increased, no change or reduced according to detection threshold based on interobserver variability."
1790,PMC4621368,S69,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,post hoc analyses of individual time points used wilcoxon tests.
1791,PMC4621368,S70,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the primary analysis included all randomised patients on an intention-to-treat basis regardless of compliance with allocated treatment and post-randomisation events.
1792,PMC4621368,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"a secondary pre-specified exploratory analysis of auc ctni release excluded patients who had myocardial infarction or a cardiac arrest, resulting in loss of cardiac output for >1 min. type v myocardial infarction was defined according to the third universal definition.18"
1793,PMC4621368,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"finally, post hoc, we examined treatment effect for each time point using the high-sensitive ctni assay."
1794,PMC4621368,S73,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,power calculations were based on a recent study of patients undergoing remote ischaemic preconditioning before coronary artery bypass surgery.5
1795,PMC4621368,S74,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"mean cardiac troponin t release quantified as auc was 36.12 µg/l (sd 26.08) and 20.58 µg/l (sd 9.58) in the control and treated patients, respectively."
1796,PMC4621368,S75,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"no contemporary auc data were available for ctni release in this patient group, but the measurements are equivalent in terms of quantifying myocardial injury."
1797,PMC4621368,S76,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"with a sample size of 80 patients, we had 90% power to detect this 40% difference in auc ctni with a significance level of 5%, using a t test with unequal variances and allowing for four dropouts in each arm."
1798,PMC4770816,S36,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,the methods used in past-bp have been reported in detail elsewhere.14
1799,PMC4770816,S37,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,past-bp was an individually randomised trial in which participants were allocated to either an intensive blood pressure target (<130 mm hg or a 10 mm hg reduction if baseline pressure was <140 mm hg) or a standard target (<140 mm hg).
1800,PMC4770816,S38,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,patients were recruited from 106 general practices (of which 99 contributed at least one patient) in england during 2009-11.
1801,PMC4770816,S39,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,patients were considered for inclusion if they were on the practice’s tia/stroke register.
1802,PMC4770816,S40,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"they were excluded if their baseline systolic blood pressure was less than 125 mm hg, they were already taking three or more antihypertensive agents, they had a greater than 20 mm hg postural change in systolic blood pressure on standing, they were already being treated to a 130 mm hg systolic blood pressure target, they were unable to provide informed consent, or there was insufficient corroborative evidence that they had had a stroke or tia."
1803,PMC4770816,S41,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,potentially eligible participants were identified using a search of the general practice’s clinical computer system.
1804,PMC4770816,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,a general practitioner reviewed this list to exclude patients for whom a study invitation would be inappropriate.
1805,PMC4770816,S43,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"the remainder were sent a letter inviting them to attend a study clinic appointment held at their general practice by a research nurse, where written informed consent was obtained."
1806,PMC4770816,S45,"['10', '8b']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Randomisation and masking,"the central study team at the university of birmingham randomised patients, with minimisation based on age, sex, diabetes mellitus, atrial fibrillation, baseline systolic blood pressure, and general practice."
1807,PMC4770816,S46,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,the research nurse ascertained treatment allocation either by telephone or online.
1808,PMC4770816,S47,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Randomisation and masking,neither participants nor clinicians were blinded to treatment allocation.
1809,PMC4770816,S48,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Randomisation and masking,a research nurse who was not otherwise involved in the patient’s care obtained the primary outcome measure (blood pressure) by using an automated sphygmomanometer.
1810,PMC4770816,S50,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,patients randomised to the intensive arm were given a target systolic blood pressure of below 130 mm hg or a target reduction of 10 mm hg if their baseline blood pressure was between 125 and 140 mm hg.
1811,PMC4770816,S51,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"the target in the standard arm was less than 140 mm hg, irrespective of baseline blood pressure."
1812,PMC4770816,S52,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"apart from the different blood pressure targets, the management of blood pressure was the same in both groups and was carried out by a practice nurse (to monitor blood pressure) and a general practitioner (responsible for modifying blood pressure treatment)."
1813,PMC4770816,S53,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,patients whose systolic blood pressure at baseline was above target (everyone in the intensive arm and those patients in the standard arm whose blood pressure was ≥140 mm hg) had their antihypertensive treatment reviewed by their general practitioner.
1814,PMC4770816,S54,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,a practice nurse would see all patients at three month intervals (if their blood pressure was below target when previously measured) or after one month (if previous blood pressure was above target) and refer to the general practitioner if the blood pressure was above target.
1815,PMC4770816,S55,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"the protocol required no formal down-titration of treatment if blood pressure was below target, but general practitioners had discretion to change or reduce treatment in the light of symptoms attributable to blood pressure drugs."
1816,PMC4770816,S56,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,we provided general practitioners with treatment protocols that reflected the national guidelines for blood pressure lowering in operation at the time of the trial.15
1817,PMC4770816,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Procedures,"in both arms of the trial, the general practitioners had access to a computer based algorithm that actively suggested drugs and dosage if the participant was above target."
1818,PMC4770816,S58,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Procedures,follow-up ceased if the participant had a major cardiovascular event.
1819,PMC4770816,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,the primary outcome was change in systolic blood pressure between baseline and one year.
1820,PMC4770816,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,participants had blood pressure measured by a research nurse (separate from the practice nurse’s measurements described above) at baseline and at six and 12 months.
1821,PMC4770816,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,blood pressure was measured using a british hypertension society validated automated electronic monitor supplied and validated for the study.16
1822,PMC4770816,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"blood pressure was measured in a standardised way, with the patient seated for five minutes and then six measurements taken at one minute intervals."
1823,PMC4770816,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,the primary outcome was the average of the second and third measurements.
1824,PMC4770816,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"secondary measures of blood pressure included diastolic blood pressure at six and 12 months, systolic blood pressure at six months, and proportion achieving target blood pressures at 12 months."
1825,PMC4770816,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Procedures,"for the systolic blood pressure, we also calculated the means of readings 2-6 and 5-6 to look for any differential effects with regard to habituation to blood pressure measurement."
1826,PMC4770816,S66,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,we identified clinical events through review of the general practice record at 12 months.
1827,PMC4770816,S67,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,"these comprised major cardiovascular events (composite of fatal and non-fatal stroke, myocardial infarction, fatal coronary heart disease, or other cardiovascular death), emergency hospital admissions, and deaths."
1828,PMC4770816,S68,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,participants were flagged for mortality at the nhs central register.
1829,PMC4770816,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Procedures,side effects were assessed through the use of standard questionnaires.14
1830,PMC4770816,S71,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"we estimated that a sample size of 305 patients in each group would detect a 5 mm hg difference in systolic blood pressure between groups with 90% power at a significance level of 5% assuming a standard deviation of 17.5 mm hg, 10% loss to follow-up, 5% mortality, and 10% major vascular events.5 7"
1831,PMC4770816,S72,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we used mixed models for the primary analysis, adjusting for baseline blood pressure, age group (<80 years, ≥80 years), sex, diabetes mellitus, atrial fibrillation, and practice (as a random effect)."
1832,PMC4770816,S73,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the principal analysis was a complete case analysis.
1833,PMC4770816,S74,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we also explored the potential effects of missing values by the use of three approaches: multiple imputation, group mean, and last available value."
1834,PMC4770816,S75,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"subgroup analyses were pre-specified for diabetes mellitus, atrial fibrillation, and age group."
1835,PMC4770816,S76,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"in addition, we did a subgroup analysis by baseline systolic blood pressure (<140 mm hg, ≥140 mm hg)."
1836,PMC4770816,S77,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we compared the number of consultations, treatment changes, and side effects by using generalised mixed modelling, adjusting for the same variables as in the primary outcome."
1837,PMC4770816,S78,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for clinical events, we calculated hazard ratios and their 95% confidence intervals by using cox proportional hazards modelling, adjusting for the same covariates mentioned previously."
1838,PMC4770816,S79,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we checked the proportional hazard assumption with schoenfeld residual plots and by including interaction terms in the model (for each term by time).
1839,PMC4770816,S80,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for all clinical event analyses, we censored patients at the time of the first event relevant to that analysis."
1840,PMC4770816,S81,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"thus, if a patient had more than one emergency hospital admission, only the first one would be counted."
1841,PMC4770816,S82,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we used sas 9.2 and stata 12 for analyses.
1842,PMC4770816,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient involvement,the study was discussed by a stroke survivor group who agreed that it was an important research question and that blood pressure was an important outcome for them.
1843,PMC4770816,S85,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient involvement,patients were involved in developing plans for recruitment and design of the study through representation on the trial steering committee.
1844,PMC4770816,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient involvement,no patients were asked to advise on interpretation or writing up of the results.
1845,PMC4770816,S87,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patient involvement,we plan to disseminate the results of the research to the relevant patient community through local and nationally organised stroke groups.
1846,PMC3420230,S101,['6b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0]",Outcomes,"once the decision not to fund the main trial was known, a full statistical analysis plan was prepared with prespecified primary and secondary outcome measures; this was uploaded onto the trials website, with the date of amendment logged."
1847,PMC3420230,S102,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,no data were unblinded before this time.
1848,PMC3420230,S103,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"for the ursodeoxycholic acid comparison, the primary outcome was itch in the mother, measured as the arithmetic mean of all post-randomisation measures of worst itch in the previous 24 hours assessed on a visual analogue scale."
1849,PMC3420230,S104,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,"to avoid over-interpretation of our results, we carried out two online surveys (www.surveymonkey.com) before unblinding of the trial to determine what reduction in score on the visual analogue scale would be a clinically meaningful difference among clinicians involved in treating women with intrahepatic cholestasis of pregnancy and among women who had previously experienced the condition (full questions given in supplementary appendix 1)."
1850,PMC3420230,S105,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,women and clinicians were informed that the mean baseline itch score on the visual analogue scale was 60 mm (by analysis of blinded data) and were offered a choice of answers.
1851,PMC3420230,S106,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"for the timing of delivery comparison, the primary outcome was caesarean section."
1852,PMC3420230,S107,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,"it is widely believed that induction in general increases the rate of caesarean sections, although recent trials of timing of delivery at term have shown no significant effect.12 13"
1853,PMC3420230,S108,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,secondary outcome measures for the ursodeoxycholic acid comparison were prespecified as maternal outcomes and perinatal outcomes.
1854,PMC3420230,S109,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"maternal outcomes were average itch in past 24 hours (visual analogue scale); levels of total bile acids, alanine transaminase, and aspartate transaminase; mode of onset of labour; mode of delivery; indication for delivery; and blood loss at delivery."
1855,PMC3420230,S110,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"perinatal outcomes were gestation at delivery, baby outcome, birth weight, presence of meconium stained amniotic fluid, arterial cord ph, venous cord ph, apgar score at five minutes, congenital anomalies, admission to a neonatal unit (including duration), need for ventilation (including duration), convulsions, and jaundice."
1856,PMC3420230,S111,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"for the timing of delivery comparison, we chose the same secondary maternal and perinatal outcomes."
1857,PMC3420230,S112,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,"the outcome measures previously specified at the start of this initial phase of the trial were designed to measure the feasibility of the second phase—namely, recruitment to the two interventions (total recruitment rate per 1000 deliveries per annum and total recruitment rate per eligible women), recruitment rates related to disease severity, acceptability of randomisation among potential participants offered trial entry, adherence with each treatment arm, and completeness of outcome data."
1858,PMC3420230,S114,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Parallel audit,all centres undertook an audit in parallel with the trial from the start of recruitment until 1 april 2010 (when the initial target of 90 women had been recruited).
1859,PMC3420230,S115,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Parallel audit,"they identified all pregnant women with raised bile acid levels (in collaboration with each hospital’s chemical pathology laboratory) and undertook postnatal case note review to ascertain whether a diagnosis of intrahepatic cholestasis of pregnancy had been confirmed, what treatment had been given, and whether the participation in the trial had been offered."
1860,PMC3420230,S116,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Parallel audit,the number of deliveries per centre per month during the audit period was obtained.
1861,PMC3420230,S118,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"for the planned factorial trial, we estimated that a provisional sample size would be 1498 women (749 per group)."
1862,PMC3420230,S119,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"this would give 80% power, α 0.05, to show a reduction in the primary composite endpoint (fetal death or severe morbidity) from 6% to 3%."
1863,PMC3420230,S120,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"however, detailed power calculations were not possible without an accurate estimate of the event rate and the clinical spectrum of likely recruits to such a trial."
1864,PMC3420230,S121,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,the target sample size of the initial phase was determined to be about 90 participants to allow reasonably precise estimates of the variables for the main trial.
1865,PMC3420230,S122,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"after the decision to analyse the initial phase alone and before unblinding, we undertook a sample size calculation based on our new primary outcome measure of maternal itch score with the clinically meaningful difference as determined."
1866,PMC3420230,S123,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,this confirmed that the study as carried out had over 99.9% power to detect a difference of 30 mm (with a standard deviation of 26 mm across both arms and a correlation between baseline and follow-up measurements).
1867,PMC3420230,S125,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"trial analysis followed the intention to treat principle, with women and infants analysed according to the original randomised allocation, irrespective of adherence and crossovers."
1868,PMC3420230,S126,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for repeated measurements over time (severity of itch and biochemistry), we used the average (arithmetic or geometric mean) during the intervention period.19"
1869,PMC3420230,S127,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"in all analyses, regression methods were used and adjustment made for stratification variables (gestation at recruitment for ursodeoxycholic acid trial only, and study centre for both trials) and for potential confounders (baseline bile acid levels, and others where the imbalance was substantial)."
1870,PMC3420230,S128,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,for the analysis of perinatal outcomes we treated all infants (singletons or twins) equally.
1871,PMC3420230,S129,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"to allow for multiple pregnancy, we adjusted standard errors for clustering by mother using the huber-white sandwich estimator, and multiplicity included as a covariate.20"
1872,PMC3420230,S130,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,mode of delivery was expressed as a perinatal outcome owing to the inclusion of twin pregnancies in which the mode of delivery may be different for one twin.
1873,PMC3420230,S131,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,for continuous outcomes (such as visual analogue scale measurement and biochemical results) covariates included the baseline measurement.21
1874,PMC3420230,S132,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,because of the spread and distribution of values we based the analysis of biochemical markers on logged values.
1875,PMC3420230,S133,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the treatment effect was presented as a concentration ratio (the ratio between treatment groups of the geometric mean concentration post-randomisation).
1876,PMC3420230,S134,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,we estimated risk ratios and risk differences for yes or no outcomes; we used binary regression with a log-link (for risk ratios) and a linear link (for risk differences).
1877,PMC3420230,S135,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,time to delivery was treated as partially censored data and analysed using cox’s proportional hazards.
1878,PMC3420230,S136,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for the ursodeoxycholic acid comparison, censoring was at delivery (if after 37 weeks) for pregnancies randomised to the early term delivery arm of the other trial and undergoing induction of labour or caesarean section owing to trial allocation (rather than maternal or fetal compromise or the request of the mother or obstetrician); and otherwise at 40 weeks."
1879,PMC3420230,S137,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for the timing of delivery comparison, censoring was at 40 weeks in all cases."
1880,PMC3420230,S138,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for subgroup analyses, the principal subgroup was level of bile acids at baseline (continuous and in three categories: normal with raised alanine transaminase levels (bile acids 14 µmol/l, alanine transaminase >100 u/l), mild (bile acids 15-40 µmol/l), and severe (bile acids >40 µmol/l)."
1881,PMC3420230,S139,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"we used interaction tests to determine whether apparent differences in treatment effect between groups could be interpreted as real (not due to chance only), and hence to indentify subgroups that might or might not benefit from randomised treatment."
1882,PMC3420230,S140,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"analyses were done in the statistical package stata version 11.1 or later (statacorp, college station, tx)."
1883,PMC3420230,S142,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Ethical approval,the protocol22 was published at the start of the trial.
1884,PMC3420230,S143,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Ethical approval,the updated statistical analysis plan was uploaded onto the trials website before unblinding of the data and incorporated into the revised protocol.
1885,PMC3420230,S144,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Ethical approval,the trial is reported in accordance with the consolidated standards of reporting trials guidelines.
1886,PMC3420230,S54,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,we undertook a semifactorial randomised controlled trial of two interventions in women with intrahepatic cholestasis of pregnancy at nine maternity units in the united kingdom.
1887,PMC3420230,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,the trial began in two centres in october 2008 and the remainder joined in over the following year as regulatory approvals were obtained.
1888,PMC3420230,S56,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"women were eligible if they had confirmed intrahepatic cholestasis of pregnancy (itching in pregnancy with other causes excluded, in association with a serum bile acid level greater than the upper limit of normal for that unit’s laboratory) or if they had pruritus with raised alanine transaminase levels (>100 iu/l) and were between 24+0 and 40+6 weeks pregnant for the ursodeoxycholic acid comparison or between 34+1 and 37+6 weeks with a singleton pregnancy for the timing of delivery comparison."
1889,PMC3420230,S57,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"we excluded women who were aged less than 18 years; had laboratory confirmed hepatitis a or hepatitis b, pre-eclampsia, primary hepatic disorders, known α-1 antitrypsin deficiency, or current drugs causing deranged liver enzymes; were known to have a lethal fetal anomaly; had an allergy to any component of the ursodeoxycholic acid or placebo capsules; or were unable to give informed consent."
1890,PMC3420230,S58,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"women with concurrent hepatitis c or cholelithiasis, or both, were eligible."
1891,PMC3420230,S59,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,women with a multiple pregnancy were eligible only for the ursodeoxycholic acid comparison as most participating clinicians indicated that such women should normally be delivered at 38 weeks’ gestation.
1892,PMC3420230,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"clinicians and midwives approached women attending the antenatal clinic, the antenatal day assessment units, or the antenatal ward about participating in the study."
1893,PMC3420230,S62,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"a member of the research team confirmed eligibility, gave the women detailed verbal information and an information sheet and invited them to take part."
1894,PMC3420230,S63,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,the usual hospital interpreter and translator services were available.
1895,PMC3420230,S64,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"the participants provided written, dated informed consent, and the women’s consultant obstetricians and general practitioners were informed of their participation."
1896,PMC3420230,S65,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"a member of the research team confirmed participant eligibility and entered an agreed minimum amount of pre-randomisation registration data on a secure internet based data form about the participant before randomisation, including the results of routine biochemical blood tests."
1897,PMC3420230,S66,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,randomisation occurred through the nottingham clinical trials unit using a web based database and randomisation system.
1898,PMC3420230,S67,"['8a', '8b']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Recruitment and randomisation,"the random allocation sequence for each comparison was generated by using a specific function (-ralloc-) in stata (statacorp, college station, tx) software within the clinical unit using randomly varying block sizes of two, four, and six."
1899,PMC3420230,S68,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Recruitment and randomisation,the random allocation sequence was not revealed until all data outcomes had been collected and the statistical analysis plan registered.
1900,PMC3420230,S69,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Recruitment and randomisation,randomisation was stratified by the gestation at recruitment for the ursodeoxycholic acid comparison and by trial centre for both comparisons.
1901,PMC3420230,S70,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Recruitment and randomisation,randomisation for both comparisons within the trial was in a 1 to 1 allocation ratio.
1902,PMC3420230,S71,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,women who were eligible for both were permitted to participate in either or both factorial comparisons.
1903,PMC3420230,S72,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"those who participated in the drug comparison before 34 weeks’ gestation were not allowed to join the timed delivery comparison until 34 weeks, so for that group, randomisation to the two treatment comparisons occurred at different times."
1904,PMC3420230,S73,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,allocation occurred centrally at the clinical unit using a web based database.
1905,PMC3420230,S74,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"on randomisation, the clinical unit’s internet trial system issued a unique participant identification number and the participant was randomised to one or both trials according to eligibility."
1906,PMC3420230,S75,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,sequentially numbered containers were sent to the clinical trial’s pharmacist at each centre at the start of the trial and all packs kept in the pharmacy until distribution to the participant.
1907,PMC3420230,S76,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"after randomisation to the ursodeoxycholic acid or placebo comparison, an online prescription form was generated for printing."
1908,PMC3420230,S77,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Recruitment and randomisation,the participant collected the trial drug or placebo from the hospital pharmacy once the local trial’s pharmacist had selected the pack with the appropriate number.
1909,PMC3420230,S78,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"the investigator, pharmacist, and trial participant were blind to group allocation."
1910,PMC3420230,S79,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"for the timing of delivery comparison, the investigator and participant could not be blinded to the treatment group and appropriate arrangements were made for induction or elective delivery or expectant management as allocated."
1911,PMC3420230,S80,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"obstetricians were permitted to induce participants in the expectant management group from 40+0 weeks’ gestation, or as clinical needs dictated."
1912,PMC3420230,S81,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,"other than the trial randomisation, women were managed in accordance with each unit’s guideline for intrahepatic cholestasis of pregnancy, with frequency of blood testing and fetal monitoring determined by the local clinicians."
1913,PMC3420230,S82,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Recruitment and randomisation,all centres were aware of the royal college of obstetricians and gynaecologists’ guidelines for management of obstetric cholestasis.8
1914,PMC3420230,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Follow-up,"after randomisation, a member of the research team saw participants weekly at the time of their routine clinical visit."
1915,PMC3420230,S85,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Follow-up,"the participant was asked about adherence to treatment, use of other drugs, and adverse events, and completed the visual analogue scale for itching."
1916,PMC3420230,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Follow-up,results of routinely collected biochemical tests were recorded.
1917,PMC3420230,S87,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Follow-up,participants were seen six weeks after delivery.
1918,PMC3420230,S88,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Follow-up,"all maternal and perinatal outcomes were collected by review of postnatal case notes, with adjudication where necessary by the trial management group."
1919,PMC3420230,S89,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Follow-up,participants were able to withdraw from the trial at either their own request or the discretion of the treating clinician.
1920,PMC3420230,S90,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Follow-up,"if a participant’s clinical condition deteriorated (for example, worsening of itch, increasing bile acid levels), the clinician could decide to stop the trial drug and give ursodeoxycholic acid, or deliver the woman if indicated, without breaking the treatment code."
1921,PMC3420230,S92,"['11b', '5']","[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Interventions,"women in the first comparison were randomised to ursodeoxycholic acid (250 mg dose; ursofalk, dr falk pharma, buckinghamshire), or to placebo capsules (dr falk pharma) identical in appearance and taste to the study drug (white, opaque, hard gelatin capsule)."
1922,PMC3420230,S93,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Interventions,the placebo contained lactose monohydrate and magnesium stearate.
1923,PMC3420230,S94,['11b'],"[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Interventions,"all capsules were packaged and labelled to provide blinded treatment packs in the production unit of the pharmacy department, nottingham university hospitals nhs trust."
1924,PMC3420230,S95,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Interventions,supplies were packed in an approved container and tagged with a single panel label.
1925,PMC3420230,S96,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Interventions,"the participant’s name, randomisation number, and date of dispensing were added to the label as part of the dispensing process."
1926,PMC3420230,S97,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Interventions,all women received two capsules twice a day and if there was no clinical improvement (itching) or biochemical improvement (serum bile acids or alanine transaminase levels) the dose was increased in increments of two capsules per day every 3-14 days up to a maximum of 2 g/day.
1927,PMC3420230,S98,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Interventions,"women in the second comparison were randomised to early term delivery (induction or delivery started between 37+0 and 37+6) or to expectant management (where spontaneous labour was awaited or caesarean delivery undertaken according to normal obstetric guidelines, usually after 39 weeks’ gestation)."
1928,PMC3420230,S99,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Interventions,"by consensus, obstetricians could arrange delivery in the latter group from 40+0 weeks’ gestation."
1929,PMC3944682,S100,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Analysis,"the likelihood ratio test is particularly useful for assessing the effect of variables with multiple levels (for example, the delayed prescribing factor, with five levels), and provides an overall test of whether the variable makes a significant difference to the statistical model."
1930,PMC3944682,S101,"['12a', '7b']","[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Analysis,"analysis was intention to treat (that is, practitioners or patients were analysed in their intended randomisation groups, whether or not they complied), but we did not impute missing values, there was no interim analysis, and no clinical subgroups for antibiotic prescribing strategies were specified in advance."
1931,PMC3944682,S33,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of study design and trial groups,"this study was a pragmatic open factorial trial of delayed antibiotic strategies, controlling for symptomatic advice regarding analgesia and steam, with a parallel observational component for patients judged to need immediate antibiotics."
1932,PMC3944682,S34,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of study design and trial groups,"health professionals, who were mainly doctors but also some practice nurses, decided in negotiation with patients whether immediate antibiotics were needed."
1933,PMC3944682,S35,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Summary of study design and trial groups,"if antibiotics were not needed, patients were randomised to one of four delayed prescribing groups: recontact for a prescription, post-dated prescription, collection of the prescription, or patient led (that is, the patient was given the prescription)."
1934,PMC3944682,S36,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of study design and trial groups,the figure and web appendix 1 provides more detail on these groups.
1935,PMC3944682,S37,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of study design and trial groups,consort flow diagram.
1936,PMC3944682,S38,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of study design and trial groups,"of 889 patients considered, 556 were judged not to require immediate antibiotics and were randomised."
1937,PMC3944682,S39,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of study design and trial groups,*numbers based on general practitioner reports
1938,PMC3944682,S40,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Summary of study design and trial groups,each group was randomised further into 12 subgroups according to three factors.
1939,PMC3944682,S41,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Summary of study design and trial groups,"these factors were antipyretic regimens (ibuprofen, paracetamol, or both combined), regular antipyretic versus “as required” dosing, and steam inhalation advice versus no advice to inhale with steam."
1940,PMC3944682,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of study design and trial groups,the web figure uses an example group (no prescription) to illustrate this randomisation process.
1941,PMC3944682,S43,['3b'],"[0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of study design and trial groups,"during the trial (from january 2011), a strategy of no antibiotic prescription was added as a randomised comparison, bringing the total number of randomised groups to five (fig 1)."
1942,PMC3944682,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,"we chose a factorial design for the analgesic and steam components to deal with the management of symptoms, and the antibiotic component particularly to deal with antibiotic use and beliefs in antibiotics."
1943,PMC3944682,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,"the factorial design is not only efficient in assessing multiple interventions, but also provides better control of symptomatic advice (regarding analgesia or steam) that could plausibly affect symptom control in the antibiotic groups."
1944,PMC3944682,S48,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,a non-randomised immediate prescription group was chosen to allow all patients to enter the study and provide two important opportunities.
1945,PMC3944682,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,"firstly, to observe how often immediate antibiotics are thought necessary by clinicians, and secondly, to be able to compare patient outcomes in those prescribed and not prescribed antibiotics."
1946,PMC3944682,S50,['3b'],"[0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,"during the study, it became clear from systematic reviews that delayed prescribing might result in higher antibiotic use than no initial prescription.8"
1947,PMC3944682,S51,['3b'],"[0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,"we therefore added a no prescription group to facilitate interpretation of the effect of delayed prescription compared with the alternatives strategies, particularly because both the delayed and no prescription groups in the current study had higher antibiotic use than in previous studies."
1948,PMC3944682,S53,"['8a', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Summary of rationales,a statistician independent of the study team coordinated the randomisation using computer generated random numbers.
1949,PMC3944682,S54,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,"if the doctor thought that immediate antibiotics were definitely required, they prescribed antibiotics, otherwise patients were randomised to one of four methods of delayed antibiotic prescribing."
1950,PMC3944682,S55,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,we assessed evidence of subversion of randomisation by monitoring the order of use of envelopes (there was no evidence of selective envelope use) and the baseline table (which showed that the groups were well balanced).
1951,PMC3944682,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,a key concern in complex pragmatic factorial trials is keeping the logistics simple and avoiding errors at the point of intervention delivery.
1952,PMC3944682,S57,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Summary of rationales,"we made it very simple to execute randomisation and delivery because the health professional took the next pack off the shelf that contained pre-randomised advice sheets (that is, there was no requirement—and hence no error—in finding and using the correct advice sheets)."
1953,PMC3944682,S58,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,"with careful attention to practitioner equipoise, this method of randomisation to different advice strategies has proved successful in previous trials.11 13 14"
1954,PMC3944682,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,there was no evidence of subversion in the current study—either for selective envelope use or bias in patient characteristics.
1955,PMC3944682,S61,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,the study included patients aged 3 years and over presenting to a health professional (a general practitioner or nurse).
1956,PMC3944682,S62,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,"patients had to present in a general practice setting with a respiratory tract infection diagnosed by the health professional (acute cold, influenza, sore throat, otitis media, sinusitis, croup, or lower respiratory tract infection)."
1957,PMC3944682,S63,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,patient or parental written consent was given.
1958,PMC3944682,S64,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,"patients were excluded if they were asthmatic (unless ibuprofen or aspirin previously provided no problems), had active or previous peptic ulceration, were hypersensitive to analgesics, and were unable to complete outcome measures (for example, they were visually impaired, had psychosis, or were severely depressed)."
1959,PMC3944682,S65,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Summary of rationales,"exclusion also applied to patients who required hospital admission (for example, for meningitis, severe pneumonia, epiglottitis, or kawasaki disease), had a known immune deficiency, or were pregnant or breastfeeding."
1960,PMC3944682,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the primary outcome was symptom severity measured at the end of each day during days 2-4 of a two week symptom diary (days 2-4 are when symptoms of all respiratory infections are at their worst11 14).
1961,PMC3944682,S68,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,we chose symptom severity as a key outcome because the most recent systematic review documented worse symptom control with delayed prescription.8
1962,PMC3944682,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the diary was completed by patients (or children) until symptoms returned to normal.
1963,PMC3944682,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"it used previously validated formats11 15 for rating symptoms (0=no problem, 6=as bad as it could be)."
1964,PMC3944682,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"symptoms included feeling generally unwell, sleep disturbance, fever, interference with normal activities, sore throat, cough, short of breath, facial or sinus pain, earache, and runny or blocked nose."
1965,PMC3944682,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,symptom resolution was a secondary outcome because duration differs according to the particular respiratory infection.7
1966,PMC3944682,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,patients were telephoned (on days 2-3) to check for any problems with diary completion.
1967,PMC3944682,S74,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Outcomes,"if no diary was received after two weeks, one mailed reminder was sent and then a phone call made as necessary to document key outcomes using a brief questionnaire—which we have shown to be reliable.13"
1968,PMC3944682,S75,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcomes,secondary outcomes were:
1969,PMC3944682,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"any antibiotic use in the 14 days after recruitment, as documented in the diary or the brief questionnaire"
1970,PMC3944682,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"side effects (rash, diarrhoea, vomiting, or abdominal pain) documented in the diary"
1971,PMC3944682,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,mean temperature readings in the morning and evening using tempadot thermometers (orally where possible)
1972,PMC3944682,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,duration of symptoms: rated moderately bad or worse
1973,PMC3944682,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"return with new or worsening symptoms or complications of intervention—that is, a patient returning with a symptom or diagnosis of respiratory tract infection recorded using a structured proforma by a member of the research team."
1974,PMC3944682,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"complications were defined as a new consultation documented in the notes within one month with otitis media, sinusitis, pneumonia, quinsy, cervical adenitis, meningitis, or septicaemia"
1975,PMC3944682,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"belief in the effectiveness of antibiotics and satisfaction, measured in the main diary using previously developed questions13"
1976,PMC3944682,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,general practitioners were asked to complete non-recruitment logs and a questionnaire at the end of the study documenting the common reasons for non-recruitment of eligible patients and for eligible patients who declined.
1977,PMC3944682,S85,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size calculation ,we calculated the sample size based on an α value of 0.05 and β value of 0.2 using the nquery program for multiple group sample sizes.
1978,PMC3944682,S86,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size calculation ,"there were two elements to the calculation, firstly for symptom control (the primary outcome), and secondly for antibiotic use."
1979,PMC3944682,S87,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size calculation ,we assumed a standard deviation of 1.1 for our primary outcome.11 13 15
1980,PMC3944682,S88,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size calculation ,"assuming that one analgesic group had symptom control that was 0.5 standard deviations better than one of the other groups (that is, a moderate effect size), 228 patients were needed to allow for 12 groups and 80% follow-up, or 504 patients for 0.33 standard deviations."
1981,PMC3944682,S89,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size calculation ,"this effect size was equivalent to one in three people rating symptoms as mild rather than moderate, agreed as a modest effect size by the trial steering committee of a medical research council funded trial of prescribing strategies for acute cough11)."
1982,PMC3944682,S90,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Sample size calculation ,"for the antibiotic outcome of the antibiotic strategies (a key outcome for this component of the study), we compared the difference in antibiotic use between the delayed strategies and no antibiotic prescription."
1983,PMC3944682,S91,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size calculation ,"seventy two patients per group or 450 in total were needed in the groups with no prescription or delayed prescription, allowing for 20% loss to follow-up."
1984,PMC3944682,S92,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size calculation ,"these numbers also assumed 15% use of antibiotics in the no antibiotic group, and 20-35% use in the delayed prescription groups (20%, 25%, 35%, and 35% for recontact, post-date, collection, and patient led, respectively)."
1985,PMC3944682,S93,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size calculation ,we estimated that 72 patients per group would provide 80% power to detect a difference of 0.5 standard deviations in symptom control between delayed prescription groups and the no prescription group.
1986,PMC3944682,S95,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Analysis,we performed an analysis of the randomised groups and a secondary analysis that included the non-randomised immediate group.
1987,PMC3944682,S96,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Analysis,"we used analysis of covariance for a factorial study for the main continuous outcomes, controlling for stratification, analgesic and steam strategies, and confounders if appropriate."
1988,PMC3944682,S97,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Analysis,"logistic regression was used for antibiotic use and return to the surgery, and cox regression was used for the duration of symptoms."
1989,PMC3944682,S98,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Analysis,odds ratios were converted to risk ratios using standard formulas.16
1990,PMC3944682,S99,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Analysis,"the effect of antibiotic strategies, and interactions, were assessed using the likelihood ratio χ2 test."
1991,PMC4797126,S100,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,sample size determination
1992,PMC4797126,S101,"['3a', '7a']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical methods,we planned to randomize 560 patients to one of three dose regimens of quilizumab or placebo in a 1:1:1:1 ratio (140 patients per group).
1993,PMC4797126,S102,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical methods,"this sample size provided approximately 84 % power to detect a 50 % reduction in average exacerbation rates due to quilizumab, assuming 0.63 exacerbations per patient in the placebo group over a 36-week treatment period, and a significance level of α = 0.10."
1994,PMC4797126,S103,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical methods,"this sample size also provided approximately 70 % power to detect a 50 % reduction in average exacerbation rates in the subgroup of periostin-high patients, assuming 0.69 exacerbations per patient in the placebo group over the 36-week period, a significance level of 0.15, and 50 % of patients in each treatment arm to be periostin high."
1995,PMC4797126,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,methods
1996,PMC4797126,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,trial design
1997,PMC4797126,S46,"['3a', '4b', '4a']","[0, 0, 0, 0, 0, 0, 1, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,"the costa trial of quilizumab was a phase ii, randomized, double-blind, placebo-controlled study (including recruiting sites from 14 countries: argentina, belgium, bulgaria, canada, germany, hungary, mexico, new zealand, peru, poland, romania, russia, ukraine, and the united states) that enrolled 578 adults with uncontrolled allergic asthma."
1998,PMC4797126,S47,"['3a', '8a', '5']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 1, 0, 0]",Trial design,patients were randomly assigned (1:1:1:1) to one of three dosing regimens of quilizumab or placebo using an interactive web response system.
1999,PMC4797126,S48,['8b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0]",Trial design,"randomization was stratified based on serum periostin level (<50 ng/ml, ≥50 ng/ml), exacerbation history (number of exacerbations (1, >1) requiring use of systemic corticosteroids in the prior 18 months), ige level (≤75 iu/ml, 75–200 iu/ml, >200 iu/ml), and country."
2000,PMC4797126,S49,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,patients and study site personnel were blinded to treatment assignments until all follow-up data through week 84 were collected and verified.
2001,PMC4797126,S50,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Trial design,"quilizumab (genentech, inc., south san francisco, ca) was delivered subcutaneously at nine monthly intervals at 300 mg per dose (300 mg m), or at three quarterly intervals and at week 4 at 150 or 450 mg per dose (150 or 450 mg q)."
2002,PMC4797126,S51,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Trial design,the treatment period ended 36 weeks after randomization and was followed by a 48-week period to assess the sustained efficacy and safety of quilizumab (see additional file 1: figure s1).
2003,PMC4797126,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,"ethics, consent, and permissions"
2004,PMC4797126,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,"quorum review based in seattle, wa was the primary central irb used by sites in north america, however multiple other site-specific institutional review boards at other global sites approved the protocol and patients gave written, informed consent."
2005,PMC4797126,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Trial design,"the trial was conducted in full conformance with the international conference on harmonisation e6 guidelines and the declaration of helsinki, or laws and regulations of the country where the research was conducted, whichever afforded greater protection to the individual."
2006,PMC4797126,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,participants
2007,PMC4797126,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,inclusion criteria
2008,PMC4797126,S57,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"adult asthma patients, aged 18–75 years, were required to have: bronchodilator reversibility of either ≥12 % β-agonist reversibility using 4 puffs of a short-acting β − agonist (saba) or a pc20 fev1 methacholine (provocative concentration of methacholine producing a 20 % fall in fev1 (forced expiratory volume in 1 s)) of 8 mg/ml or less, within the last 2 years; a pre-bronchodilator fev1 at screening of 40–80 % predicted; daily use of ics (≥400 μg/day total daily dose of fluticasone propionate or equivalent) and a second controller for a minimum of 3 consecutive months; inadequately-controlled asthma as documented by a 5-item asthma control questionnaire (acq-5) [21] score ≥1.50 at screening and randomization, despite compliance with asthma controller therapy; at least one positive aeroallergen-specific ige (≥0.35 ku(a)/l), or a total serum ige ≥75 iu/ml; and a history of at least one protocol-defined asthma exacerbation in the 18 months prior to screening."
2009,PMC4797126,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Participants,"asthma exacerbations were defined as new or increased asthma symptoms (wheezing, cough, chest tightness, shortness of breath, or nighttime awakening due to symptoms) that led to treatment with systemic corticosteroids for at least 3 days or to hospitalization."
2010,PMC4797126,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,exclusion criteria
2011,PMC4797126,S60,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Participants,"patients were excluded from the study if they had an asthma exacerbation requiring systemic steroids in the 30 days prior to screening, or between screening and randomization, a >20 % relative change in fev1 between screening and randomization, any pre-existing active lung disease other than asthma, any infections, elevated ige levels for reasons other than allergy, or were former or current smokers."
2012,PMC4797126,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Outcome measures,outcome measures
2013,PMC4797126,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measures,the primary efficacy outcome was the annualized rate of protocol-defined asthma exacerbations from baseline to week 36.
2014,PMC4797126,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measures,"secondary efficacy outcomes included assessments of lung function using the relative change in pre-bronchodilator fev1 from baseline to weeks 12 and 36 and the change in asthma symptoms from baseline to week 36, using total and daytime symptom severity scores derived from a daily patient diary."
2015,PMC4797126,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measures,the diary was also used to determine the proportion of patients who had no nighttime awakenings due to asthma symptoms and the proportion of patients with fewer than 2 days of saba use per week by week 36.
2016,PMC4797126,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measures,"exploratory outcome measures included the change in asthma control from baseline to week 36, as measured by the acq-5."
2017,PMC4797126,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measures,"to assess the change in allergy-related quality-of-life measures from baseline to week 36, the standardized asthma quality of life questionnaire (aqlq(s)) [22] and the standardized rhinoconjunctivitis quality of life questionnaire (rqlq(s)) [23] were administered at patient visits throughout the treatment and follow-up periods."
2018,PMC4797126,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measures,"we also evaluated the ability of biomarkers (serum periostin, blood eosinophils, exhaled no, and serum ige) to predict benefit from quilizumab."
2019,PMC4797126,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome measures,safety outcomes were assessed throughout the 36-week treatment and 48-week follow-up periods.
2020,PMC4797126,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Assessments,assessments
2021,PMC4797126,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"the patient daily diary included two sections in addition to peak flow measurements: 1) a morning section capturing awakenings and rescue medication use at night, and symptoms on awakening; and 2) an evening section capturing daytime symptom severity, rescue medication use, preventive inhaler use, activity impairment during the day, and nasal symptoms."
2022,PMC4797126,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"the modified total asthma symptom score (mtass) was generated from a subset of diary questions adapted from a previous questionnaire [24], scoring nighttime awakenings (0–3), symptoms on awakening (0–1), and daytime symptom severity (0–4), for a total score range of 0–8."
2023,PMC4797126,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"for the analyses of symptom scores, rescue medication use, and nighttime awakenings, daily scores were averaged over the previous 7 days prior to the time point of interest."
2024,PMC4797126,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,baseline values were derived from a minimum of 10 days of patient diary entries during the 14 days prior to the first treatment.
2025,PMC4797126,S74,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Pharmacokinetics and immunogenicity,pharmacokinetics and immunogenicity
2026,PMC4797126,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Pharmacokinetics and immunogenicity,"serum levels of quilizumab for pharmacokinetic assessments were measured using a validated enzyme-linked immunosorbent assay (elisa; genentech, inc., south san francisco, ca)."
2027,PMC4797126,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Pharmacokinetics and immunogenicity,"the pharmacokinetic outcomes included: serum concentrations prior to dosing at weeks 0, 4, 12, 24, and 32; serum concentrations at week 5 and week 25; maximum observed serum concentrations (cmax,obs); time of maximum observed serum concentration (tmax, obs); and terminal elimination half-life (t1/2)."
2028,PMC4797126,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Pharmacokinetics and immunogenicity,"serum anti-therapeutic antibodies (atas) were assessed in samples at weeks 0, 4, 12, 24, 36, 48, 60, and 84 using a validated bridging elisa (genentech, inc., south san francisco, ca)."
2029,PMC4797126,S78,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Biomarkers,biomarkers
2030,PMC4797126,S79,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Biomarkers,samples for biomarker assessments were collected throughout the study.
2031,PMC4797126,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Biomarkers,"allergen-specific and total ige were measured in serum by immunocap® specific ige blood tests (viracor-ibt laboratories, lee’s summit, mo)."
2032,PMC4797126,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Biomarkers,"specific ige was measured for the following allergens: cat, house dust mite (hdm) dermatophagoides farinae, hdm dermatophagoides pteronyssinus, ragweed, aspergillus, timothy grass, bermuda grass, oak, birch, plantain, and orchard grass."
2033,PMC4797126,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Biomarkers,the maximum specific ige was defined as the specific ige with the highest titer of specific iges pre-dose in each patient.
2034,PMC4797126,S83,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Biomarkers,"only observed values of ige levels were analyzed, with no imputation performed for missing ige data."
2035,PMC4797126,S84,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Biomarkers,peripheral blood eosinophil counts were obtained from standard complete blood counts.
2036,PMC4797126,S85,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Biomarkers,"serum periostin was measured by immunoassay using the roche elecsys platform (roche diagnostics ltd., rotkreuz, switzerland)."
2037,PMC4797126,S86,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Biomarkers,"fractional exhaled nitric oxide (feno) was measured using a hand-held portable device, niox mino® (niox; morrisville, nc), according to american thoracic society/european respiratory society 2009 guidelines [25]."
2038,PMC4797126,S87,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,statistical methods
2039,PMC4797126,S88,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"all patients received at least one dose of study drug (intention-to-treat, itt population) and were included in all safety and efficacy analyses."
2040,PMC4797126,S89,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,demographic and baseline characteristics were summarized using descriptive statistics.
2041,PMC4797126,S90,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical methods,"the primary endpoint, the annualized exacerbation rate, was calculated by the total number of protocol-defined exacerbations observed in the group over the treatment period divided by total patient-weeks at risk (number of weeks from first study drug administration to the earliest of week 36 or study discontinuation) for the group and multiplied by 52."
2042,PMC4797126,S91,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"for patients who discontinued the study prematurely, there was no imputation of additional exacerbations."
2043,PMC4797126,S92,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"the rates of asthma exacerbations were compared between study groups using a poisson regression with overdispersion model, including terms for periostin status (<50, ≥50 ng/ml), number of prior exacerbations (1, >1), and ige level (<200, ≥200 iu/ml)."
2044,PMC4797126,S93,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"for biomarker subgroup analyses, unadjusted asthma exacerbation rates were calculated."
2045,PMC4797126,S94,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,corresponding two-sided p-values and 90 % confidence intervals (ci) were reported.
2046,PMC4797126,S95,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,the relative change in pre-bronchodilator fev1 from baseline was calculated as the absolute change in fev1 (volume in liters) from baseline divided by the fev1 at baseline.
2047,PMC4797126,S96,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"for secondary and exploratory end points, the means and standard deviations of all values for relative change were calculated according to study group at weeks 12 and 36."
2048,PMC4797126,S97,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"the mean relative changes from baseline were compared between the study groups using the differences between the means for each group, with the associated two-sided 90 % cis."
2049,PMC4797126,S98,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"missing values were imputed using the last-observation-carried-forward (locf) approach, as prespecified in the statistical analysis plan."
2050,PMC4797126,S99,"['12a', '12b']","[0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"an analysis of covariance (ancova) model with factors for baseline level, periostin status (<50 ng/ml, ≥50 ng/ml), number of prior exacerbations (1, >1), and ige level (<200 iu/ml, ≥200 iu/ml) was fit to assess the treatment effect."
2051,PMC4893154,S27,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population,vindicate was a randomized placebo-controlled double-blind trial of vitamin d supplementation in vitamin d−deficient chronic hf patients on optimal medical therapy.
2052,PMC4893154,S28,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population,"patients were eligible if they had stable (>3 months) new york heart association functional class ii or iii symptoms, a left ventricular ejection fraction (lvef) ≤45% on maximally tolerated medical therapy (>3 months) and a 25(oh) vitamin d level of <50 nmol/l (<20 ng/ml)."
2053,PMC4893154,S29,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population,"patients were ineligible if they were taking or had taken calcium or other vitamin supplements in the last 3 months; if their chronic hf was due to untreated valvular heart disease, anemia or thyrotoxicosis; if they had existing indications for vitamin d supplementation (e.g., previous osteoporotic fracture or symptoms of osteomalacia); if they had a history of primary hyperparathyroidism, sarcoidosis, tuberculosis or lymphoma, a cholecalciferol concentration at the time of screening >50 nmol/l (20 ng/ml); or if there was significant renal dysfunction (estimated glomerular filtration rate <30 ml/min)."
2054,PMC4893154,S31,"['8b', '8a']","[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Allocation and intervention,"patients enrolled into vindicate were allocated in blocks of 20 using minimization balancing for etiology of chronic hf (ischemic/non-ischemic), diabetes mellitus, sex, chronic obstructive pulmonary disease (requiring use of regular bronchodilators), and ethnic origin (caucasian/non-caucasian)."
2055,PMC4893154,S32,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Allocation and intervention,"each participant was asked to take 2 tablets per day providing either a total of 100 μg cholecalciferol (4,000 iu daily) or placebo (cultech, port talbot, wales, united kingdom)."
2056,PMC4893154,S33,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Allocation and intervention,the supplement and dose were chosen based upon guidelines for studies of vitamin d supplementation (17).
2057,PMC4893154,S34,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Allocation and intervention,"these guidelines suggest that studies should: 1) aim to replace physiological requirements, supplementing between 75 and 250 μg/day; 2) last at least 9 months; 3) supplement with vitamin d3 (not d2); 4) assay supplements for potency; 5) include a regular serum measurement of 25(oh)d3 levels; and 6) aim to achieve serum levels in patients on active therapy between 100 and 160 nmol/l (40 ng/ml to 64 ng/ml)."
2058,PMC4893154,S35,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Allocation and intervention,"also, on the basis of recent data demonstrating the adverse effect of hyperparathyroidism in chronic hf (18), we chose a dose likely to suppress parathyroid hormone (pth) release."
2059,PMC4893154,S36,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Allocation and intervention,"our proof of concept study, using the same inclusion and exclusion criteria and protocol as vindicate, had previously demonstrated the efficacy of 4,000 iu daily to achieve positive remodeling with significant reductions in left ventricular end-diastolic volume (lvedv), left ventricular end-systolic volume (lvesv), and left ventricular end-diastolic dimension (lvedd)."
2060,PMC4893154,S37,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Allocation and intervention,"the consort diagram and results from this study are presented in online supplementary datasets (online figure 1, online tables 1 and 2)."
2061,PMC4893154,S38,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Allocation and intervention,"a simple linear model-based trend test from this study demonstrated a significant decrease in pth over the year (p = 0.0095) in those allocated vitamin d, with no such trend in patients allocated to the placebo arm (p = 0.977) (online figure 2) (19)."
2062,PMC4893154,S40,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome variables,the pre-specified primary endpoint in vindicate was the difference in change in 6-min walk test distance (6mwt) (baseline to 12 months) between the 2 groups.
2063,PMC4893154,S41,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcome variables,"key pre-specified secondary endpoints included cardiac structure and function, and safety endpoints of serum calcium concentration, renal function, and vitamin d levels. hypervitaminosis d was defined as 25(oh)d3 >200 nmol/l (80 ng/ml), and hypercalcemia as >2.6 nmol/l (10.4 mg/dl)."
2064,PMC4893154,S43,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study procedures,at baseline each patient performed a 6mwt according to standard criteria (20).
2065,PMC4893154,S44,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study procedures,"each patient also underwent echocardiography and blood sampling for serum calcium, serum creatinine, vitamin d, and pth levels."
2066,PMC4893154,S45,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study procedures,patients were also invited to undergo cardiac magnetic resonance (cmr) imaging to measure lv volumes.
2067,PMC4893154,S46,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Study procedures,"subsequent visits took place at 3, 6, 9, and 12 months and blood draws were repeated at each visit for safety data."
2068,PMC4893154,S48,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Serum biochemistry,serum 25(oh)d2 and 25(oh)d3 were analyzed by tandem mass spectrometry.
2069,PMC4893154,S49,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Serum biochemistry,samples were prepared using a protein precipitation reagent containing deuterated cholecalciferol.
2070,PMC4893154,S50,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Serum biochemistry,"the supernatant was analyzed on an api5000 lc-ms/ms (ab sciex, warrington, united kingdom) in atmospheric-pressure chemical ionization mode."
2071,PMC4893154,S51,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Serum biochemistry,the inter-assay coefficient of variability was <10% at all concentrations ranging from 12 nmol/l to 159 nmol/l (4.8 ng/ml to 63.7 ng/ml).
2072,PMC4893154,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Serum biochemistry,"ergocalciferol and cholecalciferol concentrations were summed and reported as total 25(oh)d. we defined deficiency and insufficiency of vitamin d concentrations as <50 nmol/l (20 ng/ml) and <75 nmol/l (30 ng/ml), respectively 21, 22."
2073,PMC4893154,S53,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Serum biochemistry,"we also measured serum calcium, creatinine, and pth (siemens advia and centaur, siemens healthcare diagnostics, camberley, united kingdom)."
2074,PMC4893154,S54,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Serum biochemistry,"to confirm effective conversion of the supplement, we also measured 1,25(oh)d3 by radioimmunoassay (ids, boldon, united kingdom) at baseline and 12 months."
2075,PMC4893154,S56,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Echocardiography,echocardiography was performed on all patients at baseline and lv function was assessed according to european society of cardiology criteria using simpson’s biplane measure to determine lvef (23).
2076,PMC4893154,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Echocardiography,echocardiography was repeated at 12 months.
2077,PMC4893154,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Echocardiography,echocardiograms at both time points were analyzed offline at the end of the study by 2 senior echocardiographers blinded to patient treatment.
2078,PMC4893154,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",CMR imaging,"cmr studies were performed on dedicated 1.5-t or 3-t cmr systems (philips healthcare, best, the netherlands)."
2079,PMC4893154,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",CMR imaging,the same system was used for baseline and follow-up studies (at 12 months) of individual patients.
2080,PMC4893154,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",CMR imaging,"a multislice multiphase data set covering the entire left ventricle in 10 to 12 short axis slices was acquired using a validated 2-dimensional balanced steady-state free precession pulse sequence (tr 2.8 ms, te 1.4 ms, flip angle 55°, spatial resolution 2.0 mm × 2.0 mm × 10 mm, no interslice gap, 30 phases/cardiac cycle, 1 slice per breath-hold)."
2081,PMC4893154,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",CMR imaging,"offline analysis by an experienced cmr observer using qmass v7.0 software (medis, leiden, the netherlands) blinded to study allocation derived end-diastolic and end-systolic lv volumes and lvef."
2082,PMC4893154,S65,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,vindicate was powered to provide information on the patient-oriented outcome of 6mwt.
2083,PMC4893154,S66,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,a trial of iron supplementation in a similar patient group had demonstrated that improvements of 30 m to 40 m could be expected with this type of intervention (24).
2084,PMC4893154,S67,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,"we assumed, based upon our preliminary data from a pilot study (19), that there would be a change between the 2 groups at 12 months of 30 m."
2085,PMC4893154,S68,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,the sd of change in 6mwt was estimated from these data; the upper limit of the 80% confidence interval (ci) (estimated using bootstrapping) was used in these calculations to allow for the small sample size in the proof of concept.
2086,PMC4893154,S69,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,this determined that 210 patients were required to have 90% power to show a difference in change in 6mwt of 28 m or more with 5% significance (sd = 62).
2087,PMC4893154,S70,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size,we aimed to recruit 230 patients (115 per group) to allow for ∼10% dropout.
2088,PMC4893154,S72,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,differences in baseline variables between allocations were tested using student t tests (continuous data) or the chi-square test (categorical data).
2089,PMC4893154,S73,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"the analysis of primacy for the main efficacy endpoints was based on analysis of covariance linear models relating differences in the final walk distance and imaging variables by treatment allocation, adjusting for baselines values and reported with 95% cis (25)."
2090,PMC4893154,S74,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,all significance tests were 2-sided and called significant at the 5% level.
2091,PMC4893154,S75,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all analyses were conducted in stata (version 14, statacorp., college station, texas)."
2092,PMC4893154,S77,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Ethical and safety considerations,a single unblinded observer with no involvement in the patients’ care or study follow-up (j.h.b.) reviewed each vitamin d result at each time point for safety.
2093,PMC4893154,S78,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Ethical and safety considerations,an agreed operating procedure for any subject who developed a serum vitamin d concentration >200 nmol/l (80 ng/ml) involved reducing the dose of treatment from 2 to 1 tablets per day to maintain patient blinding.
2094,PMC4902320,S160,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,supplemental digital content
2095,PMC4902320,S39,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,this was a randomized controlled trial.
2096,PMC4902320,S40,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,the protocol was approved by the study hospital's human research ethics committee and registered with the australian new zealand clinical trials registry (actrn12611000387921).
2097,PMC4902320,S41,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,we randomly allocated participants (1:1) to either perioperative intravenous (iv) iron administration (intervention) or usual care.
2098,PMC4902320,S42,['8a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",METHODS,randomization followed a computer-generated number sequence and allocation was conducted by telephone.
2099,PMC4902320,S43,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,the surgeon performing the operation was informed of patient participation in the study but group allocation was not revealed.
2100,PMC4902320,S44,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,we screened 626 patients scheduled for abdominal surgery for the presence of ida between august 2011 and november 2014.
2101,PMC4902320,S45,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"after informed written consent, patients eligible for inclusion (>18 yrs with ida, ferritin <300 mcg/l, transferrin saturation <25%, hb <12.0 g/dl for women, hb <13.0 g/dl for men) were randomized between 4 and 21 days before surgery into 2 groups."
2102,PMC4902320,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"owing to this wide range in the preoperative period between patients, a standard approach was used to assess transfusion events in the preoperative period, including any transfusion administered in the 21 days before surgery."
2103,PMC4902320,S47,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,"patients in the intervention group received iv ferric carboxymaltose, given as a single dose over 15 minutes, before surgery (simplified dosing protocol; 15 mg/kg bodyweight to a maximum dose of 1000 mg)."
2104,PMC4902320,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,"postoperatively, within 2 days of surgery, intervention group participants received 0.5 mg of ferric carboxymaltose per recorded 1 ml of blood loss, if blood loss was at least 100 ml."
2105,PMC4902320,S49,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,blood loss was measured as accurately as possible by recording suction bottle volume and weighing packs at the end of the operation.
2106,PMC4902320,S50,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,"patients in the usual care group received perioperative care, including anemia management, provided by the primary care physician or surgical home team."
2107,PMC4902320,S51,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,"usual care provided included no treatment, continued observations, oral iron recommendations, and abt."
2108,PMC4902320,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,"at the time of initiation of the study, iv iron was not considered usual care; however, prescription and administration was not disallowed."
2109,PMC4902320,S53,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,"in the institution, the prescription and administration of the intervention was facilitated by the anesthetic team."
2110,PMC4902320,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,baseline testing of the short form health survey (sf36) was conducted at study entry.28
2111,PMC4902320,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,follow-up of participants was scheduled for 4 weeks after surgery.
2112,PMC4902320,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",METHODS,the sf36 and screening bloods were repeated at this time.
2113,PMC4902320,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",METHODS,"patients found to have noteworthy id or ida at follow-up, irrespective of group allocation, were referred to their general practitioner for ongoing management."
2114,PMC4902320,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Quality Control Procedure,a trial information session was given to the departmental members involved before commencing the study.
2115,PMC4902320,S60,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Quality Control Procedure,regular refreshers were scheduled to assure protocol knowledge and adherence.
2116,PMC4902320,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Quality Control Procedure,the multidisciplinary composition of the research team facilitated this process.
2117,PMC4902320,S62,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Quality Control Procedure,"follow-up and data entry were meticulously conducted by a research assistant, and primary care physician follow-up and care initiated when necessary to assure patient safety."
2118,PMC4902320,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,the primary endpoint was incidence of abt.
2119,PMC4902320,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"secondary endpoints included hemoglobin (hb) on admission, hb difference from randomization to admission, icu admission, perioperative morbidity (defined as new onset infection, respiratory failure, renal impairment, deep venous thrombosis), discharge hb, length of stay, hb at follow-up, hb difference from discharge to follow-up, iron status, 30-day mortality, and quality of life (qol)."
2120,PMC4902320,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Outcomes,"qol score was scaled from 36 to 160, with lower scores reflecting poorer well-being."
2121,PMC4902320,S68,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical Analysis,the sample size of this study was calculated for the primary outcome parameter (perioperative allogeneic transfusion event).
2122,PMC4902320,S69,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical Analysis,"to reduce the risk of a perioperative allogeneic transfusion event from 30% to 15% (a 50% risk reduction) with a power of β = 0.8 and a significance level of α = 0.05, it was determined that a total of 121 patients in each group would be needed."
2123,PMC4902320,S70,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical Analysis,"to account for possible dropouts, we intended to include 134 patients per group."
2124,PMC4902320,S71,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical Analysis,"the power calculation was performed using nquery advisor version 7.0 (statistical solutions, saugus, ma)."
2125,PMC4902320,S72,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical Analysis,"parametric data were tested with one-way anova, and are presented as mean and standard error of the mean or as mean and 95% confidence intervals."
2126,PMC4902320,S73,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical Analysis,"nonparametric data were tested with mann-whitney u tests, and are reported as either median (iqr) or median (minimum–maximum), as indicated."
2127,PMC4902320,S74,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical Analysis,"categorical data were analyzed with the 2-tailed pearson χ2 test, and are presented accordingly as number and percent of total."
2128,PMC4902320,S75,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical Analysis,"statistical analysis was performed using spss software version 17.0 (spss inc, chicago, il)."
2129,PMC5009486,S44,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,male and female patients of 40–80 years of age with a diagnosis of copd as defined by the american thoracic society (ats) [11] and a smoking history of at least 10 pack-years were included in the study.
2130,PMC5009486,S45,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"key lung function criteria for inclusion were pre- and post-short-acting bronchodilator (ipratropium bromide; atrovent® hfa) forced expiratory volume in 1 s (fev1)/forced vital capacity (fvc) ratio <0.7, post-bronchodilator fev1 ≥30 % and <80 % of the predicted value and ≥750 ml at screening (visit 1), and a pre-bronchodilator fev1 <80 % at randomization (visit 2) calculated using the third national health and nutrition examination survey (nhanes iii) reference equations [12]."
2131,PMC5009486,S46,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"key exclusion criteria were diagnosis of asthma, α1-antitrypsin deficiency, or any other respiratory disease."
2132,PMC5009486,S47,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,poorly controlled copd that had required hospitalization or treatment with systemic corticosteroids within 3 months or antibiotics within 6 weeks prior to screening (visit 1) also led to exclusion.
2133,PMC5009486,S48,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"in addition, patients with clinically significant abnormal electrocardiogram (ecg) results; pregnant or lactating women; and patients who could not meet ats criteria for acceptable spirometry results were excluded [13]."
2134,PMC5009486,S49,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients using oral β-agonists, inhaled labas, laba/ics combination inhalers, phosphodiesterase inhibitors, mast cell stabilizers, leukotriene antagonists, or tiotropium, discontinued these for the duration of the trial and instead received open-label ipratropium four times daily during the run-in period."
2135,PMC5009486,S50,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients using ics/laba fdc inhalers who had received a stable dose for at least 4 weeks prior to screening were switched to the corresponding dose of a single ics agent, such as fluticasone, mometasone or budesonide administered bid for the remainder of the study."
2136,PMC5009486,S51,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients receiving a maintenance dose of an ics that was not administered as a fdc were permitted to continue, provided they had been maintained on a stable dose for at least 4 weeks prior to screening."
2137,PMC5009486,S52,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,"other prohibited medications included non-selective β-receptor antagonists, tricyclic antidepressants, monoamine oxidase inhibitors, anticonvulsants, and phenothiazines."
2138,PMC5009486,S54,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,"this was a randomized, incomplete-block, crossover, placebo- (blinded) and active- (open-label) control study (nct01566773), conducted at 10 sites in the usa from 11 april 2012 to 10 august 2012."
2139,PMC5009486,S55,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,"six doses of gp mdi (18, 9, 4.6, 2.4, 1.2, and 0.6 μg), administered bid for 14 days, were assessed."
2140,PMC5009486,S56,"['11b', '11a']","[0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,investigators and patients were blinded to gp mdi and placebo mdi treatment using non-distinguishable mdis.
2141,PMC5009486,S57,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,open-label tiotropium (18 μg; spiriva® handihaler®) dpi administered once daily (qd) was included as an active control.
2142,PMC5009486,S58,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,"in this study, gp is expressed as the salt, glycopyrrolate (glycopyrronium bromide), where a dose of 18 μg is equivalent to 14.4 μg glycopyrronium (active moiety)."
2143,PMC5009486,S59,['8a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Study design and treatment,"following screening, patients were randomized using an interactive web response system to one of 120 pre-defined treatment sequences, comprising four out of the eight possible treatments."
2144,PMC5009486,S60,"['5', '3a']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,"each treatment period was 14 days, separated by a 7- to 21-day washout period (fig. 1)."
2145,PMC5009486,S61,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,fig. 1 study design schematic.
2146,PMC5009486,S62,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,rand randomization; pft pulmonary function test; rx treatment
2147,PMC5009486,S63,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,"at each study visit and prior to performing any study procedures, patients had to confirm that they had withheld all copd medication for at least 6 h, or the visit was rescheduled as soon as practical and within the specified visit windows."
2148,PMC5009486,S64,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,"during the study, albuterol sulfate (salbutamol hfa; ventolin®) mdi was permitted as needed for relief of symptoms."
2149,PMC5009486,S65,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,"during screening and washouts between treatment periods, ipratropium bromide (atrovent® hfa) mdi was used as maintenance medication."
2150,PMC5009486,S66,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and treatment,"this study was conducted in accordance with international conference on harmonization guidelines, the declaration of helsinki [14], and the us code of federal regulations."
2151,PMC5009486,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"patients attended scheduled clinic visits at screening (visit 1), randomization (visit 2), then on days 1, 7, and 14 of each treatment period."
2152,PMC5009486,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"all pulmonary function tests, including fev1, fvc and inspiratory capacity (ic) as defined in ats guidelines, were performed in accordance with ats criteria [13]."
2153,PMC5009486,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,spirometry was performed to assess lung function pre- and post-dose at each study visit.
2154,PMC5009486,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"the assessed time points on days 1 and 7 of each treatment period were 60 and 30 min pre-dose and 15, 30, 60, and 120 min post-dose."
2155,PMC5009486,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"on day 14, post-dose time points were assessed up to 12 h post-dose."
2156,PMC5009486,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"safety evaluations included heart rate, diastolic blood pressure, and ecgs, conducted at every clinic visit."
2157,PMC5009486,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,blood samples were taken pre- and post-dose on days 1 and 14 of each treatment period to perform laboratory assessments including hematology and blood chemistry.
2158,PMC5009486,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"adverse events (aes) and serious aes were documented by investigators, with paradoxical bronchospasm and dry mouth classified as events of interest."
2159,PMC5009486,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Endpoints,the primary objective of this study was to assess efficacy relative to placebo mdi of gp mdi.
2160,PMC5009486,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Endpoints,"to this end, each dose of gp mdi was compared with placebo mdi on the primary efficacy endpoint; fev1 area under the curve from 0 to 12 h (auc0–12) relative to baseline on day 14 of each treatment period."
2161,PMC5009486,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Endpoints,fev1 auc0–12 values were normalized by dividing by the length of time over which they were obtained (typically 12 h).
2162,PMC5009486,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Endpoints,"the key secondary endpoints were time to onset of action (≥10 % improvement from baseline in fev1) on day 1; peak change from baseline in fev1 on days 1, 7, and 14; change from baseline in morning pre-dose trough fev1 on days 7 and 14; change from baseline in 12-h post-dose trough fev1 on day 14; peak change from baseline in ic on days 1, 7, and 14; mean change from baseline in morning pre-dose trough ic on days 7 and 14; and the proportion of patients achieving ≥12 % improvement in fev1 on day 1."
2163,PMC5009486,S82,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"the planned sample size was 120 patients, designed to provide approximately 93 % power to detect differences of 100 ml in fev1 auc0–12."
2164,PMC5009486,S83,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"the 100-ml difference was selected on the grounds that it is the minimum clinically important difference, defined as the change in fev1 that can be perceived by the patient [15]."
2165,PMC5009486,S84,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"the principal population for primary efficacy analyses was the modified intent-to-treat (mitt) population, comprising all patients who completed at least two treatment periods with at least 2 h of post-dose data for day 14 from both periods."
2166,PMC5009486,S85,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for the primary efficacy analysis of assessing the dose–response curve, the family-wise type i error was not controlled for multiplicity beyond specifying a primary endpoint and the six key comparisons, namely each dose of gp mdi compared with placebo mdi."
2167,PMC5009486,S86,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"to compare each dose of gp mdi with placebo mdi, a linear mixed-effects model was used with fev1 auc0–12 as the dependent variable, and baseline trough fev1, bronchodilator reversibility, period, sequence, and treatment as covariates."
2168,PMC5009486,S87,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,baseline was defined as the mean of pre-dose values obtained from the first day of each treatment cycle averaged across periods.
2169,PMC5009486,S88,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,secondary efficacy analysis for the primary efficacy endpoint assessed the non-inferiority of each treatment group to open-label tiotropium using a margin for clinical relevance of 100 ml.
2170,PMC5009486,S89,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,other secondary efficacy analyses involved superiority comparisons of secondary endpoints for each treatment group versus placebo mdi and non-inferiority comparisons versus open-label tiotropium.
2171,PMC5009486,S90,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,non-inferiority was only determined for a treatment group if the lower bound of the 95 % confidence interval (ci) for the difference was above −100 ml and if all higher dose levels were statistically significantly non-inferior to open-label tiotropium.
2172,PMC5009486,S91,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"non-inferiority testing was not performed for time to onset of action on day 1, for which cumulative incidence kaplan–meier curves were plotted."
2173,PMC5009486,S92,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,the proportion of patients achieving ≥12 % improvement from baseline on day 1 was tabulated and a logistic regression was used to compare treatments.
2174,PMC5009486,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"for safety analyses the safety population was used, defined as all patients who were randomized and received at least one dose of study treatment and had a post-baseline safety assessment for that treatment."
2175,PMC5009486,S94,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"safety and tolerability data, including laboratory parameters, vital signs and ecg results were summarized descriptively, with aes tabulated according to severity, relationship to study drug and the medical dictionary for regulatory activities system level and preferred term."
2176,PMC5033259,S31,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Research Design and Methods,"forty-eight men and women provided written informed consent to participate in this randomized, placebo-controlled, double-blind study (full details are available in supplementary fig. 1)."
2177,PMC5033259,S32,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Research Design and Methods,participants first had a screening visit at the beth israel deaconess medical center clinical research center to ensure that they met the inclusion and exclusion criteria for the study.
2178,PMC5033259,S33,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Research Design and Methods,no prior studies with lorcaserin in the human brain existed on which to base power calculations.
2179,PMC5033259,S34,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Research Design and Methods,"we thus enrolled 48 subjects, with an a priori plan to replace up to 8 subjects that would drop out (assuming up to 20% attrition)."
2180,PMC5033259,S35,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Research Design and Methods,sample size was selected to be similar to prior randomized trials of other pharmaceuticals studied using similar neuroimaging protocols.
2181,PMC5033259,S36,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Research Design and Methods,"with 80% power and 2 groups of 20 participants, we estimated that we would be able to detect an effect size difference of 0.9 at the α = 0.05 level."
2182,PMC5033259,S37,"['11b', '5']","[0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Research Design and Methods,"after the screening visit, participants were randomized 1:1 to receive oral lorcaserin (10 mg, twice daily) or placebo, which was identical in appearance to lorcaserin."
2183,PMC5033259,S38,"['8a', '8b', '11a', '10']","[0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Research Design and Methods,randomization tables were produced by the harvard catalyst biostatisticians with sas using blocks of four and delivered directly to the research pharmacy for use such that study staff would remain blinded.
2184,PMC5033259,S39,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Research Design and Methods,"the study took place over 4 weeks; participants visited the clinical research center on weeks 0, 1, 2, and 4."
2185,PMC5033259,S40,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Research Design and Methods,"the first study visit was a baseline overnight visit, which consisted of at least a 12-h fast, followed by a blood draw, vital signs, physical examination, anthropometry (waist and hip measurements), resting metabolic rate (measured with sensormedics vmax spectra), two fmri scans (one in the fasting state and another in the fed state), and neurocognitive testing."
2186,PMC5033259,S41,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Research Design and Methods,"in addition, at each visit, all participants were given the standard of care for obesity, where they met with a registered dietitian to be counseled about weight loss, with the recommendation of decreasing caloric intake by 500 kcal/day and exercising 30 min 3 days/week."
2187,PMC5033259,S42,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Research Design and Methods,"patients were also given the modified scale for suicidal ideation (mssi) by a physician at each visit to ensure they did not develop suicidal thoughts, because manipulating serotonin levels could potentially lead to changes in mood and suicidal ideation."
2188,PMC5033259,S43,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Research Design and Methods,they returned after 1 and 4 weeks for the same overnight visits.
2189,PMC5033259,S44,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Research Design and Methods,"participants also attended an outpatient follow-up visit at 2 weeks, which consisted of a physical examination and blood draw."
2190,PMC5033259,S45,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Research Design and Methods,"in between visits, patients continued to take their medication at home and kept a detailed food diary, which was discussed with the patients at each visit and analyzed by registered dietitians."
2191,PMC5033259,S46,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Research Design and Methods,fasting blood was drawn by venipuncture by a registered nurse.
2192,PMC5033259,S47,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Research Design and Methods,"samples were analyzed by labcorp, a clinical laboratory improvement amendments–certified laboratory."
2193,PMC5033259,S49,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data Analysis,data were analyzed using spss 19 software and first summarized with descriptive statistics.
2194,PMC5033259,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data Analysis,data for categorical variables are presented as numbers and/or percentages.
2195,PMC5033259,S51,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data Analysis,kolmogorov-smirnov test and frequency histograms were used to check the normality of distribution of the continuous variables.
2196,PMC5033259,S52,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data Analysis,repeated-measures anova were performed across time points with lorcaserin or placebo as a between-subjects factor.
2197,PMC5033259,S53,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data Analysis,on-treatment analysis was performed for all variables (results reported in table 1).
2198,PMC5033259,S54,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data Analysis,"intention-to-treat analysis was done with the anthropometric data only, to confirm on-treatment analysis, using the last observation carried forward method (results reported in table 2)."
2199,PMC5033259,S55,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data Analysis,table 1 results from study visits over 1 month for the lorcaserin (n = 17) and placebo (n = 19) groups
2200,PMC5033259,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Data Analysis,table 2 results from study visits over 1 month for the lorcaserin (n = 24) and placebo (n = 24) groups using intent-to-treat methods
2201,PMC5033259,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,participants viewed food and nonfood items within a 3-tesla ge mri scanner at the mri center at beth israel deaconess medical center in the fasting and fed states with an invivo therapeutics 8-channel high-definition receiver head coil.
2202,PMC5033259,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,scanning was done using a protocol similar to that previously described (18).
2203,PMC5033259,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"first, in each of the scanning sessions, a t1-weighted magnetization prepared rapid gradient echo structural mri was acquired."
2204,PMC5033259,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"next, five 7-min gradient-echo t2-weighted echo planar images depicting blood oxygenation level–dependent (bold) contrast were acquired from noncontiguous near axial planes (repetition time = 3.5 s, echo time = 25 ms, in-plane resolution = 2.5 × 2.5 mm, matrix size = 96 × 96, field of view = 24 × 24 cm, voxel bandwidth = 83.33 khz, slice thickness = 3 mm)."
2205,PMC5033259,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,e-prime software controlled stimulus presentation.
2206,PMC5033259,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"images were presented in blocks, and each block was presented in a counterbalanced order and interspersed with periods of visual fixation."
2207,PMC5033259,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"the fmri protocol consisted of five runs, during which subjects viewed blocks of highly desirable (high-calorie or high-fat images such as cakes, onion rings, and other similar foods), less desirable (low-calorie or low-fat images such as vegetables and fruits), or nonfood images (examples included flowers, rocks, and trees) and provided responses on how well they could imagine or visualize each image using a response box held in their right hand, as previously described (19,20)."
2208,PMC5033259,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"approximately 150 images were used in randomized order, presented during both the fasting and fed states."
2209,PMC5033259,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"blocks consisted of 5 images each, where each image was shown for 3 s (15 s total for each block), with 10 s of fixation/rest between blocks, and 16 blocks were shown during each of the 5 runs."
2210,PMC5033259,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"bold data were preprocessed using spm8 software (statistical parametric mapping; the wellcome trust centre of neuroimaging, london, u.k.)."
2211,PMC5033259,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"briefly, images of each individual subject were flipped, realigned (motion-corrected), normalized to an epi template with affine registration, followed by nonlinear transformation, and smoothed with a gaussian kernel of 6 mm."
2212,PMC5033259,S69,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"a general linear model was constructed for each subject, using the onsets of the food or nonfood image blocks with realignment parameters in six dimensions."
2213,PMC5033259,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,the data were high-pass filtered to remove low-frequency signal drifts.
2214,PMC5033259,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,the contrast images (highly desirable > less desirable food images; all food (highly and less desirable) > nonfood images) of the first-level analysis were used for the second-level group statistics.
2215,PMC5033259,S72,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"flexible factorials were used to compare the two groups at weeks 1 and 4, controlling for baselines (week 0)."
2216,PMC5033259,S73,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"whole-brain regressions were used to examine how brain activations at baseline (week 0) related to changes in weight, bmi, and caloric intake."
2217,PMC5033259,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"given the multiple areas studied, activations that passed a corrected threshold of p < 0.05, family-wise error (fwe) corrected for multiple comparisons for the cluster, and/or peak activation are reported."
2218,PMC5033259,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"on the basis of an a priori hypothesis for the hypothalamus, owing to findings in rodents of lorcaserin’s weight-reducing efficacy being mediated by the hypothalamus, we performed a region of interest analysis for the hypothalamus using a 10-mm radius sphere, as defined previously (19)."
2219,PMC5033259,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,"effect size data for hypothalamus and for activations, which were significantly different for week 1 > week 0 and for week 1 > week 4, contrasts were extracted using marsbar (http://marsbar.sourceforge.net/)."
2220,PMC5033259,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,effect sizes were examined between groups and over time for the hypothalamus.
2221,PMC5033259,S78,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",fMRI Protocol and Analysis,effect sizes from contrasts were correlated with changes in bmi and caloric intake using pearson correlations.
2222,PMC5064025,S44,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"novartis pharmaceuticals (cambridge, massachusetts) initiated this phase ii, double-blind, randomized, placebo-controlled trial, with the final study protocol designed in collaboration with the investigators (r.p.c., j.-c.t., and z.a.f.), based on their previously published methods 19, 23, 24."
2223,PMC5064025,S45,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"the study was undertaken at 9 centers in canada, the united kingdom, the united states, germany, and israel, in compliance with the principles of the declaration of helsinki and according to good clinical practice guidelines."
2224,PMC5064025,S46,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,"the protocol was reviewed and approved by the institutional review board, or equivalent, for each center."
2225,PMC5064025,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Methods,all participants provided written informed consent before undertaking any study procedures.
2226,PMC5064025,S49,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,patients (ages 18 to 74 years) were eligible for inclusion if they had clinically evident atherosclerotic vascular disease: previous myocardial infarction; history of angina; carotid stenosis (>30%); peripheral vascular disease (ankle–brachial index <0.9); endarterectomy >3 months previously; or transient ischemic attack or stroke.
2227,PMC5064025,S50,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"in addition, patients must also have had either t2dm (for ≤14 years and glycosylated hemoglobin [hba1c] levels between 6% and 10%) or igt (defined as a peak 2-h glucose reading ≥140 mg/dl but <200 mg/dl after an oral glucose tolerance test during screening)."
2228,PMC5064025,S51,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,patients were to have been on stable statin therapy for a period of ≥6 weeks before screening (or have physician-documented statin intolerance).
2229,PMC5064025,S52,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,"after consent, eligible patients were randomized (1:1) to receive canakinumab 150 mg or placebo, subcutaneously, monthly for 12 months."
2230,PMC5064025,S53,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"exclusion criteria included: pregnancy; systemic steroid use; baseline high-sensitivity c-reactive protein (hs-crp) levels >30 mg/l; history of significant multiple drug allergies; history or evidence of chronic infection, including tuberculosis and liver disease; or a standard contraindication to mri."
2231,PMC5064025,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,randomization occurred between december 2009 and november 2012.
2232,PMC5064025,S55,"['8a', '8b', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Patients,"patient groups were assigned centrally according to a validated computer-generated randomization code, stratified according to glycemic status (t2dm or igt)."
2233,PMC5064025,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Imaging procedures,an integrated vascular mri was performed at baseline and after 3 and 12 months of treatment.
2234,PMC5064025,S58,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Imaging procedures,"if the imaging data did not meet an evaluable standard at any time point, the patient was rescanned."
2235,PMC5064025,S59,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Imaging procedures,randomization required an evaluable baseline scan.
2236,PMC5064025,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Imaging procedures,"the imaging procedure comprised measures of aortic wall area and distensibility, as well as carotid wall area bilaterally."
2237,PMC5064025,S61,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Imaging procedures,"the imaging protocol was adapted from lee et al. (19), and staff at each imaging site underwent individualized training to ensure consistency of method and data acquisition."
2238,PMC5064025,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Imaging procedures,"all trial sites used a 3.0-t whole-body mri scanner, including trio, tim trio, or verio (siemens medical solutions usa, inc., malvern, pennsylvania) or achieva (philips, amsterdam, the netherlands) platforms."
2239,PMC5064025,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Imaging procedures,"for carotid imaging, a bilateral 4-channel carotid array (machnet b.v., roden, the netherlands) was used on the siemens scanners and an equivalent multi-channel (4 to 8) phased array carotid coil (shanghai medical, shanghai, china) was used on the philips scanners."
2240,PMC5064025,S64,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Imaging procedures,detailed information regarding imaging protocols and analysis is available in the online appendix.
2241,PMC5064025,S65,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Imaging procedures,the velocity at which the arterial pulse propagates is termed pulsed wave velocity (pwv).
2242,PMC5064025,S66,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Imaging procedures,"a measure of arterial stiffness, it is an independent predictor of mortality in both t2dm and igt (26)."
2243,PMC5064025,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Imaging procedures,the sphygmocor platform (atcor medical pty.
2244,PMC5064025,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Imaging procedures,"ltd., west ryde, australia) was applied immediately before mri scanning to acquire the aortic central pulse pressure from radial artery applanation tonometry and the pwv from the carotid-femoral pulse waves."
2245,PMC5064025,S70,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety assessments,"monitoring of vital signs, electrocardiogram, standard hematology, and biochemistry (including measurement of lipoproteins, liver function, and creatine kinase) were conducted throughout the study."
2246,PMC5064025,S71,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Safety assessments,a data monitoring committee oversaw subject safety on an ongoing basis.
2247,PMC5064025,S72,"['6a', '11a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety assessments,"in addition, 3 adjudication committees made blinded assessments of adverse events in relation to cardiac, malignant, and infection-related events."
2248,PMC5064025,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Endpoints,the primary efficacy objectives were the effects of the drug on aortic distensibility and total plaque burden in the aorta and carotid arteries; the primary safety objective was the safety and tolerability of canakinumab in this population.
2249,PMC5064025,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Endpoints,secondary objectives included the effects of canakinumab on aortic pwv; hs-crp; hba1c; homeostasis model assessment (homa)–insulin resistance; and peak blood glucose level 2 h after an oral glucose challenge.
2250,PMC5064025,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Endpoints,"exploratory analyses of peripheral biomarkers of inflammation (including il-6, serum amyloid a, and plasma lipoproteins) were also performed."
2251,PMC5064025,S78,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,sample size was calculated from the study of lee et al. (19).
2252,PMC5064025,S79,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analyses,"to detect a 35% change in aortic distensibility or an 11% change in plaque burden at 12 months to achieve a power of 0.8 and nominal p < 0.05 (2-sided), 60 patients per group were required."
2253,PMC5064025,S80,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analyses,"to ensure 120 datasets with 12-month follow-up data, it was planned to randomize 190 patients."
2254,PMC5064025,S81,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"given the exploratory nature of the study, corrections were not made for the multiplicity of statistical tests."
2255,PMC5064025,S82,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"as defined by the protocol, patients were included in the 3-month data analysis if they had no missing doses at 3 months; for the 12-month analysis, participants were required to have no missing doses by 3 months and 1 or no missing doses between 3 and 12 months."
2256,PMC5064025,S83,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"to compare treatment with placebo, we conducted an analysis of covariance on change from baseline, including the glycemic status as a factor and the baseline as a covariate at 3 and 12 months."
2257,PMC5064025,S84,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"all data were checked for normality and log-transformed, if appropriate."
2258,PMC5064025,S85,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"when a log transformation of the change from baseline was not possible because of negative values, an analysis of covariance was conducted on the log-transformed 3- and 12-month data, including glycemic index status as a factor and the log-transformed baseline as a covariate."
2259,PMC5064025,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,we considered a p value <0.05 as significant.
2260,PMC5064025,S87,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,results are reported as means with 95% confidence limits.
2261,PMC5064025,S88,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Statistical analyses,"two interim analyses were pre-specified, when n = 60 and all patients had completed 3 months of treatment, respectively, with the intention of halting the study if adverse measures were identified or for futility but not for interim positive efficacy."
2262,PMC5064025,S89,['7b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0]",Statistical analyses,the interim analyses were performed by independent personnel not directly associated with the study’s conduct.
2263,PMC5064025,S90,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,the study sponsor and funder (novartis) participated in discussions about the design and conduct of this study; they also provided the drugs used in the trial and logistical support for its execution.
2264,PMC5064025,S91,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"the trial design, endpoints, and statistical analyses were largely derived from the academic investigators’ previously published studies 19, 23, 24."
2265,PMC5064025,S92,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"following the final database lock, all patient data were analyzed independently by the centre for statistics in medicine, oxford (j.b.)."
2266,PMC5064025,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"the manuscript was drafted by the academic investigators (r.p.c., j.s.b., j.-c.t., and z.a.f.), in accordance with the written agreement between novartis and the academic institutions, and reviewed and revised by the writing committee."
2267,PMC5064025,S94,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,all authors had full access to all the data in the study and assume responsibility for publication.
2268,PMC5064025,S95,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analyses,"all statistical analyses were performed by using stata 14 (statacorp lp, college station, texas)."
2269,PMC5099201,S147,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,web supplement
2270,PMC5099201,S38,"['4a', '3a']","[0, 0, 0, 0, 0, 0, 1, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,"n this randomised, controlled study, patients with ra diagnosed according to the 1987 american college of rheumatology (acr) criteria less than 10 years before, aged between 20 and 75 years, with moderate or high disease activity at baseline visits, were enrolled between november 2009 and march 2012."
2271,PMC5099201,S39,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,"moderate or high disease activity was defined as a disease activity score in 28 joints (das28; on the basis of the erythrocyte sedimentation rate, esr) of more than 3.2."
2272,PMC5099201,S40,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,participants had to have been receiving stable doses of ≥6 mg/week of mtx for treatment of ra for at least 8 weeks before enrolment.9
2273,PMC5099201,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,"patients were excluded if they had previously taken or were taking any biologic treatment, leflunomide within 12 weeks of baseline, tacrolimus within 4 weeks, or any other conventional dmards other than mtx within 8 weeks."
2274,PMC5099201,S42,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,patients taking prednisolone (or equivalent) at a dose of more than 10 mg/day were excluded.
2275,PMC5099201,S43,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,"this report covers the planned analysis of the first 1 year of a 2-year study (nct01120366, umin000002744)."
2276,PMC5099201,S44,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,this study was approved by the ethics committee at each site and conducted in accordance with the declaration of helsinki.
2277,PMC5099201,S45,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design and participants,"all participants gave their written, informed consent."
2278,PMC5099201,S47,"['3a', '5', '8a']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 1, 0, 0, 0, 0, 1, 0, 0]",Study treatment,patients were randomly assigned by a centralised system in a 1:1 ratio to one of two open-label treatment groups: tcz added to mtx (add-on group) or tcz switched from mtx (switch group).
2279,PMC5099201,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study treatment,"tcz was administered at a dose of 8 mg/kg intravenously every 4 weeks, and mtx was maintained at the same dose as the baseline unless a clinically relevant adverse event (ae) occurred."
2280,PMC5099201,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,data collected at baseline included demographics and disease characteristics.
2281,PMC5099201,S51,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,"the following parameters were assessed at baseline and at weeks 4, 12, 24, and 52: tender joint count, swollen joint count, health assessment questionnaire-disability index, patient global assessment using a visual analogue scale (vas), evaluator global assessment using a vas, c-reactive protein (crp), esr and matrix metalloproteinase-3."
2282,PMC5099201,S52,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,radiographs of the hands and feet were obtained at baseline and at week 52.
2283,PMC5099201,S53,"['6a', '11a']","[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,each radiograph was assessed applying the van der heijde-modified total sharp scoring system (mtss) by two independent readers who were blinded to treatment assignment and the patient's clinical status.
2284,PMC5099201,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Collected patient data and assessments,"at each visit, patients were monitored for physical signs, laboratory tests, and aes."
2285,PMC5099201,S56,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,the primary outcome of this study was defined as the percentage of patients in remission according to the das28-esr at week 24.
2286,PMC5099201,S57,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical analysis,"with the assumption that das28-esr remission would be achieved by 50% of patients in the add-on group and 45% in the switch group, 133 patients per treatment group were calculated as necessary for more than 80% power to prove the null hypothesis of no difference between the treatment arms with a non-inferiority margin of 10%."
2287,PMC5099201,S58,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,a two-sided statistical test of no difference at the 5% significance level was used.
2288,PMC5099201,S59,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"as a sensitivity analysis, the percentage of patients in remission according to the simplified disease activity index (sdai) and clinical disease activity index (cdai) in substitution for the das28 was further analysed."
2289,PMC5099201,S60,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,efficacy analyses were conducted in the full analysis population with the last-observation-carried-forward method.
2290,PMC5099201,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical analysis,"safety endpoints including the incidence of aes, serious aes, infections, and specific laboratory abnormalities were analysed in all treated patients."
2291,PMC5099201,S62,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical analysis,"all analyses of proportions were analysed for treatment differences with the χ2 test, and continuous variables were compared with student's t test."
2292,PMC5264229,S188,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Supplementary Material,web supplement
2293,PMC5264229,S39,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,patients who were 18–75 years old with ra classified by the 1987 american college of rheumatology (acr) classification criteria for ra were enrolled; patients had to have had ra for at least 6 months with least six tender joints and six swollen joints; an erythrocyte sedimentation rate (esr) of ≥28 mm/h or a c reactive protein of ≥1.0 mg/dl was required.
2294,PMC5264229,S40,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,patients had to take mtx for at least 6 months and had to be under a stable dose for at least 4 weeks before randomisation.
2295,PMC5264229,S41,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"for details of inclusion and exclusion criteria, see online supplementary appendix s1."
2296,PMC5264229,S43,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"this study is a phase iii, randomised, double-blind, multinational, multicentre parallel group study (nct01936181, eudract 2012-005733-37)."
2297,PMC5264229,S44,['3a'],"[0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"the study consists of a 54-week main study and an additional 24-week transition (switching) study; this report is about the results of the 54-week main study up to week 30 (for the graphical presentation see online supplementary appendix s2-1), which includes the primary outcome."
2298,PMC5264229,S45,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,patients were randomised in a 1:1 ratio to receive either sb2 or inf of 3 mg/kg intravenously.
2299,PMC5264229,S46,"['10', '8a']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Study design,"randomisation and treatment allocation was implemented through an interactive web responsive system (cenduit llc, see online supplementary appendix s3-1)."
2300,PMC5264229,S47,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"infusion of sb2 or inf was done over 2 h; dosing was done at each visit at week 0, week 2, week 6, week 14, week 22, week 30, week 38 and week 46."
2301,PMC5264229,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"dose increases could occur from week 30 by 1.5 mg/kg per visit, up to a total of 7.5 mg/kg."
2302,PMC5264229,S49,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the final visit for the main study occurred at week 54.
2303,PMC5264229,S50,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"to prevent infusion related reactions (irrs), premedications such as corticosteroids, antihistamines or paracetamol were allowed per investigator discretion."
2304,PMC5264229,S51,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,mtx was given as an oral or parenteral weekly dose of 10–25 mg/week with folic acid of 5–10 mg/week.
2305,PMC5264229,S52,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,non-steroidal anti-inflammatory drugs and corticosteroids (≤10 mg prednisolone) were allowed if taken for a stable dose for 4 weeks before randomisation.
2306,PMC5264229,S53,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,other disease modifying antirheumatic drugs except for mtx were prohibited during the study.
2307,PMC5264229,S54,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"all patients were screened for tuberculosis (tb) by medical history, chest x-ray and quantiferon-tb gold in-tube tests (qiagen); quantiferon tests were done at screening, week 22 and week 54."
2308,PMC5264229,S55,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,patients with active tb were ineligible for the study and those who were found to have latent tb had to undergo prophylaxis according to country-specific guidelines to enrol in or continue with the study.
2309,PMC5264229,S56,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the study was conducted in 73 centres in 11 countries from europe and asia.
2310,PMC5264229,S57,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the study was conducted according to the declaration of helsinki and good clinical practice issued by the international committee on harmonisation.
2311,PMC5264229,S58,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,all patients gave formal written informed consent before participating in the study.
2312,PMC5264229,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"efficacy, safety and immunogenicity assessments for all patients were done at each visit before sb2 or inf infusion."
2313,PMC5264229,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,the primary end point of the study was the acr 20% (acr20) response at week 30 in the per-protocol set (pps).
2314,PMC5264229,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"other secondary efficacy end points included acr50 and acr70, disease activity score measured by 28 joints-erythrocyte sedimentation rate (das28-esr) and european league against rheumatism (eular) response."
2315,PMC5264229,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,a post hoc analysis of simplified disease activity index (sdai) and clinical disease activity index (cdai) was done to measure the proportion of patients achieving low disease activity (lda) or remission.15 16
2316,PMC5264229,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"efficacy components such as tender and swollen joint counts, visual analogue scales scores and health assessment questionnaire of disability index scores were assessed before each infusion."
2317,PMC5264229,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"safety assessments included monitoring of vital signs, physical examination, laboratory assessments and reports of adverse events (aes)."
2318,PMC5264229,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"aes were collected in particular for serious aes, serious infections or tb and irrs."
2319,PMC5264229,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,immunogenicity assessments were done by measuring serum antidrug antibodies (adas) to infliximab at each visit before infusion.
2320,PMC5264229,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,ada-positivity was defined as those who had at least one positive ada result up to week 30.
2321,PMC5264229,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Assessments,"this was a prespecified outcome, according to recommendations from the american association of pharmaceutical scientists.17"
2322,PMC5264229,S70,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Assessments,it accommodates all measures of ada incidence over each individual time point that may be subject to variation.
2323,PMC5264229,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,those who were ada-positive were additionally assessed for neutralising antibodies.
2324,PMC5264229,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,a single-assay approach with a sb2 tag was used to assess immunogenicity.
2325,PMC5264229,S73,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,"adas were measured using validated electrochemiluminescence immunoassays and neutralising antibodies were measured using a competitive ligand-binding assay (mesoscale discovery platform, meso scale discovery, rockville, maryland, usa)."
2326,PMC5264229,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,pk assessments were done by measuring the serum trough concentrations (ctrough) of infliximab before each infusion.
2327,PMC5264229,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Assessments,serum infliximab concentrations were determined using a validated elisa.
2328,PMC5264229,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,the primary objective was to demonstrate equivalence of acr20 at week 30.
2329,PMC5264229,S78,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size and statistical analysis,to determine equivalence between sb2 and inf the 95% ci of the acr20 rate difference had to be within the prespecified margin of −15% and +15%.
2330,PMC5264229,S79,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size and statistical analysis,the equivalence margin was determined using data from several inf studies4 18 19 and regulatory guidelines.20 21
2331,PMC5264229,S80,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size and statistical analysis,"sample size was calculated assuming this equivalence margin of ±15%, an effect size of 57% and a 20% dropout rate."
2332,PMC5264229,S81,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Sample size and statistical analysis,"with a significance level of 5% and a power of 80%, a sample size of at least 292 randomised patients per treatment group was required in order to reach the required subject size for the pps."
2333,PMC5264229,S82,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,the primary efficacy outcome was analysed using the pps and the full analysis set (fas).22
2334,PMC5264229,S83,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,fas follows the same principles of the intention-to-treat analysis; fas included all randomised patients who received at least one dose of sb2 or inf.
2335,PMC5264229,S84,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,"in addition, if missing data occurred, such patients were assumed to be acr20 non-responders in fas."
2336,PMC5264229,S85,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,"for analysis of acr20, the rate difference was adjusted by baseline c reactive protein and geographical region using a non-parametrical analysis of covariance.23–25"
2337,PMC5264229,S86,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,"analysis of acr50 and acr70 was also done in pps and fas; das28, sdai, cdai and eular response were done only in the fas (only available das28 and sdai/cdai were analysed in this case)."
2338,PMC5264229,S87,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,subgroup analysis of acr20 was done by comparing acr20 response rates within each ada subgroup (positive or negative) in a prespecified manner.
2339,PMC5264229,S88,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,"to formally test the differential influence of ada on sb2 or inf, an analysis of covariance was done including an ada-by-treatment interaction term in the model."
2340,PMC5264229,S89,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,a prespecified exponential time-response model using non-linear mixed models26 was fitted to compare the acr20 response between sb2 and inf over time (see also online supplementary appendix s3-2).
2341,PMC5264229,S90,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,"the squared differences across all time points from the two curves (2-norm) were measured, and if the upper limit of the 95% ci of the 2-norm was less than 61.80, the two curves were considered equivalent."
2342,PMC5264229,S91,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,safety results were presented as the number of patients with percentage who had a particular ae in the safety analysis set (saf; those who received at least one dose of sb2 or inf).
2343,PMC5264229,S92,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,immunogenicity results were presented as the number of patients with percentages having incident ada up to week 30 from the saf.
2344,PMC5264229,S93,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,pk assessment was done in the pk population (approximately the first enrolled 50% of the study population) up to week 30.
2345,PMC5264229,S94,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,pk results are shown as mean ctrough with sd and coefficient of variation from the pk population.
2346,PMC5264229,S95,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,"general statistical analysis was done using sas v.9.2 (sas, cary, north carolina, usa)."
2347,PMC5264229,S96,['12b'],"[0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,"pk parameters were calculated by non-compartmental analyses (winnonlin v.5.2, pharsight, mountain view, california, usa)."
2348,PMC5264229,S97,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Sample size and statistical analysis,graphical figures were made using r 3.0.1 (http://www.r-project.org).
2349,PMC5418559,S39,"['3a', '4b']","[0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"this was a multicenter, phase 2, randomized, double-blind, placebo-controlled study conducted at 79 sites in the usa (clinicaltrials.gov identifier: nct01923428) between august 2013 and october 2014 (last patient last visit july 2014)."
2350,PMC5418559,S40,['4b'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the sites conducting the study were gastroenterology practices (n=26) or primary care and research practices (n=53) specializing in internal medicine and/or gastroenterology.
2351,PMC5418559,S41,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study design,"after a 2-week screening period, eligible patients were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups: tenapanor 5 mg, 20 mg, or 50 mg twice daily (b.i.d.; dosed as the hydrochloride salt) or placebo b.i.d. patients received tenapanor or placebo for 12 consecutive weeks, after which they were followed up for an additional 4 weeks."
2352,PMC5418559,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,"patients visited the study site seven times during the study: once during the 2-week screening period (week −2), five times during the active treatment period (weeks 0, 2, 4, 8 and 12), and once more at the end of the 4-week follow-up period (week 16)."
2353,PMC5418559,S43,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study design,the study was conducted in accordance with the declaration of helsinki and all patients provided written informed consent.
2354,PMC5418559,S45,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,men and women aged 18–75 years who met the rome iii criteria for ibs-c (20) were eligible for study enrollment.
2355,PMC5418559,S46,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"in addition, patients had to have had a colonoscopy within the past 10 years if more than 50 years of age or in the presence of unexplained warning symptoms (e.g., lower gastrointestinal bleeding, iron-deficiency anemia, clinically significant weight loss, and systemic signs of infection or colitis), and agree to use appropriate methods of contraception, or be surgically sterile or post-menopausal."
2356,PMC5418559,S47,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"the main exclusion criteria were: functional diarrhea, ibs with diarrhea, mixed ibs or un-subtyped ibs, as defined by rome iii criteria; any clinically symptomatic biochemical or structural abnormality or active disease of the gastrointestinal tract within 6 months before screening; use of medications that are known to affect stool consistency (except as described below); hepatic dysfunction (defined as alanine aminotransaminase/serum glutamic-pyruvic transaminase or aspartate aminotransaminase/serum glutamic-oxaloacetic transaminase >2.5 × the upper limit of normal) or renal impairment (serum creatinine >2 mg/dl); any surgery on the stomach, small intestine or colon (excluding appendectomy); a major psychiatric disorder requiring hospitalization in the last 3 years, or a history of attempted suicide or uncontrolled bipolar disorder; or clinical evidence of any significant disease that may interfere with the patient successfully completing the trial."
2357,PMC5418559,S48,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,pregnant or lactating women were also excluded.
2358,PMC5418559,S49,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Patients,"after the 2-week screening period, in order for patients to be randomly assigned to study treatment, they needed to complete symptom assessments via a touch-tone telephone diary for at least 11 out of 14 days to ensure that they were diary compliant and meet the following study entry criteria: average weekly stool frequency of five or fewer spontaneous bowel movements (sbms), defined as all non-aided bowel movements, and two or fewer complete spontaneous bowel movements (csbms), defined as a bowel movement accompanied by a sensation of complete evacuation; an average weekly stool consistency score of 3 or less using the bristol stool form scale (bsfs) (21); an average weekly abdominal pain score of at least 3 on a 0–10-point scale; and no liquid stools for any sbm or mushy stools for more than one sbm according to the bsfs."
2359,PMC5418559,S50,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,rescue medication (bisacodyl 5 mg tablet or 10 mg suppository) was allowed for a maximum of 2 days during the screening period but not during the 48 h before randomization.
2360,PMC5418559,S51,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,"during the study, rescue medication was allowed to relieve severe constipation (defined as at least 72 h without a bowel movement or when symptoms became intolerable)."
2361,PMC5418559,S52,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,bowel movements were not considered to be sbms and csbms if they were reported <24 h after the use of rescue medication.
2362,PMC5418559,S53,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Patients,"patients who were on a stable, continuous regimen of fiber, bulk laxatives, stool softeners, and/or probiotics during the 30 days before the screening visit were included in the study and, provided that they maintained the same treatment and dose throughout the trial, were included in the analysis."
2363,PMC5418559,S55,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,the csbm responder rate was the primary efficacy variable in this study.
2364,PMC5418559,S56,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,"secondary efficacy variables included a composite of the csbm responder rate and the abdominal pain responder rate, and the responder rates for individual abdominal symptoms including abdominal discomfort, abdominal bloating, abdominal fullness, and abdominal cramping."
2365,PMC5418559,S57,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,"additional secondary efficacy variables were weekly averages of stool frequency, stool consistency, straining, abdominal pain, constipation severity, and ibs severity."
2366,PMC5418559,S58,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,"degree of relief from ibs symptoms, and treatment satisfaction at 12 weeks were additional secondary efficacy variables."
2367,PMC5418559,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,data for all efficacy variables were recorded by patients using the touch-tone telephone diary.
2368,PMC5418559,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,"variables recorded daily included stool frequency (csbms and sbms), stool consistency (bsfs), abdominal symptom scores (pain, bloating, cramping, discomfort, and fullness; each on a 0–10-point scale, 0=absent, 10=very severe), and a straining score (1–5-point scale, 1=not at all, and 5=an extreme amount)."
2369,PMC5418559,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,"variables scored weekly by patients included constipation severity, ibs severity (each on a 1–5-point scale, 1=none, 5=very severe), degree of relief from ibs symptoms (1–7-point scale, 1=completely relieved, 7=as bad as i can imagine), and treatment satisfaction (1–5-point scale, 1=not at all satisfied, 5=very satisfied)."
2370,PMC5418559,S64,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,the csbm responder rate was defined as the proportion of patients with an increase of at least one csbm/week compared with baseline for at least 6 of the 12 treatment weeks.
2371,PMC5418559,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,"the baseline value was defined as the average of the number of csbms per week for the 2-week screening period (i.e., weeks −1 and −2)."
2372,PMC5418559,S66,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,"responder rates for individual abdominal symptoms (abdominal pain, bloating, cramping, discomfort, and fullness) were defined as the proportion of patients with a decrease of at least 30% from baseline in the average weekly severity score for at least 6 out of 12 treatment weeks."
2373,PMC5418559,S67,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Efficacy variables,"a composite responder rate (22) was calculated as the proportion of patients with an increase of at least one csbm/week from baseline (primary efficacy variable) and a decrease of at least 30% from baseline in average weekly abdominal pain severity score during the same week, for at least 6 out of 12 treatment weeks."
2374,PMC5418559,S69,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Safety variables,adverse events (aes) were monitored throughout the trial.
2375,PMC5418559,S70,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Safety variables,they were reported by the patient spontaneously and/or in response to an open question from study personnel at each site visit.
2376,PMC5418559,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety variables,"safety assessments included: vital signs at each visit (systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature, and weight); clinical laboratory tests (serum electrolytes, hematology, and urinalysis) at weeks −2, 4, and 12; physical examinations at weeks −2, 12, and 16; and 12-lead electrocardiogram monitoring at weeks −2 and 12."
2377,PMC5418559,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Safety variables,"blood samples for pharmacokinetic assessments of tenapanor were collected at site visits at weeks 8 and 12, 1–4 h after morning dosing, from subsets of ~30 randomly selected patients per group."
2378,PMC5418559,S74,"['8a', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0]",Statistical methods,a computer-generated randomization scheme was made available to all clinical centers participating in the study via an interactive web response system.
2379,PMC5418559,S75,['9'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1]",Statistical methods,the packaging and labeling of the study drug kits were based on a separate drug packaging randomization schedule.
2380,PMC5418559,S76,"['8b', '8a', '10']","[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0]",Statistical methods,the interactive web response system determined which drug package the center should administer to the patient based on a randomization schedule where each treatment was allocated once using a block size of four within each study site.
2381,PMC5418559,S77,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"this ensured whole or partial block sizes were allocated, facilitating even distribution of patients amongst each dose group."
2382,PMC5418559,S78,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical methods,data collected from the touch-tone telephone diary system throughout the study were automatically entered into a database; any abnormal values were automatically flagged so the relevant site could follow-up with the patient for clarification.
2383,PMC5418559,S79,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,compliance to study treatment was determined based on the amount of unused study drug returned to study sites.
2384,PMC5418559,S80,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,the intention-to-treat analysis set included all patients who received at least one dose of study drug/placebo and for whom at least one valid week of efficacy assessment data had been collected.
2385,PMC5418559,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical methods,a valid week required at least four non-missing days.
2386,PMC5418559,S82,"['6a', '12a']","[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical methods,"scores for stool frequency were standardized to 7 days, with missing days during the week being imputed with the average for the non-missing days."
2387,PMC5418559,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Statistical methods,the average weekly scores for other efficacy variables were calculated from the observed number of responses without any standardization.
2388,PMC5418559,S84,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,the safety analysis set included all patients who received at least one dose of study drug or placebo.
2389,PMC5418559,S85,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical methods,a sample size of 90 patients in each treatment group was expected to provide 80% power to detect a difference of 20% in the csbm responder rate between the placebo group and at least one of the tenapanor treatment groups.
2390,PMC5418559,S86,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistical methods,an assumed responder rate of 20% in patients treated with placebo was based on historical data from a similar trial in patients with ibs-c (23); an assumed responder rate of 40% in patients treated with tenapanor was considered to be clinically meaningful in this patient population.
2391,PMC5418559,S87,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"the primary efficacy variable, the csbm responder rate, was analyzed using a cochran–mantel–haenszel (cmh) test with pooled investigator sites as a stratification variable."
2392,PMC5418559,S88,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,a closed testing procedure was used to control the experiment-wise type i error rate at the 5% significance level.
2393,PMC5418559,S89,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"a cmh screening test was conducted first (for the primary efficacy variable only) to look for an association between treatment and responder rate across the placebo, tenapanor 20 mg b.i.d., and tenapanor 50 mg b.i.d. treatment groups."
2394,PMC5418559,S90,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"if the result of this test was found to be statistically significant at the 5% level, each of the tenapanor 20 mg b.i.d. and 50 mg b.i.d. treatment groups were compared with the placebo group using a 5% significance level."
2395,PMC5418559,S91,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"if either or both of these comparisons were found to have a significant result, either or both of these treatment groups were considered to be individually or simultaneously significantly different from the placebo group."
2396,PMC5418559,S92,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"if both the tenapanor 20 mg b.i.d. and tenapanor 50 mg b.i.d. treatment groups were significantly different from the placebo group, the tenapanor 5 mg b.i.d. treatment group was compared with the placebo group using a 5% significance level."
2397,PMC5418559,S93,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"cmh pairwise comparison tests of all tenapanor doses vs. placebo were used to evaluate the abdominal pain responder rate, the composite responder rate, and the responder rates for other abdominal symptoms (abdominal bloating, cramping, discomfort, and fullness)."
2398,PMC5418559,S94,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistical methods,"continuous efficacy variables were assessed using an analysis of covariance model with pooled investigator sites and treatment group as terms and with baseline as the covariate, or an analysis of variance model with pooled investigator sites and treatment as terms."
2399,PMC5529963,S100,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,the greenhouse-geisser correction for the f test was used to adjust the degrees of freedom for deviation from sphericity.
2400,PMC5529963,S101,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,analysis was performed using graphpad prism analysis software.
2401,PMC5529963,S102,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,a two-sided p value of <0.05 was considered to indicate statistical significance.
2402,PMC5529963,S103,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,an additional multilevel logistic regression analysis was conducted in r to confirm our results (see online supplementary appendix 2).
2403,PMC5529963,S104,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,we fit multilevel logistic regression models for measure of hdl function using the lme4 package (http://cran.r-project.org/web/packages/lme4/index.html) in the r statistical language (http://www.r-project.org/).
2404,PMC5529963,S105,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,all coefficients were taken as random effects.
2405,PMC5529963,S106,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,10.1136/heartjnl-2015-308953.supp2
2406,PMC5529963,S107,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,supplementary appendix 2
2407,PMC5529963,S36,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"we studied 18 patients with early erosive ra who were required to have (i) a diagnosis of ra according to the american college of rheumatology 1987 criteria, (ii) symptoms for 6 months—3 years, (iii) a minimum of two swollen metacarpophalangeal (mcp) joints despite treatment with mtx and (iv) seropositivity for igm rheumatoid factor."
2408,PMC5529963,S37,['4a'],"[0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"in addition, eligible patients were required to have either (i) erosion of ≥1 mcp joint as demonstrated on plain radiography or as a cortical break with irregular margins (or contour) on greyscale ultrasound in both the longitudinal and transverse scanning planes or (ii) erosions of ≥2 mcp joints (cortical breaks with irregular margins/contour on greyscale ultrasound in either the transverse or the longitudinal plane associated with a strong vascular signal in power doppler mode at the site of the cortical break).7"
2409,PMC5529963,S38,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"all patients received oral mtx for greater than or equal to at least 8 weeks, at a minimum stable dosage of 12.5 mg/week but not exceeding 17.5 mg/week."
2410,PMC5529963,S39,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,patients being treated with oral corticosteroids must have been receiving a stable dosage (10 mg prednisolone per day) for 4 weeks.
2411,PMC5529963,S41,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,vascular properties of hdl from 18 patients with ra were compared with 18 healthy control subjects.
2412,PMC5529963,S42,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"healthy controls had no cv risk factors by history, clinical examination and laboratory tests, and were matched to patients with ra for age and gender."
2413,PMC5529963,S44,['11a'],"[0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"all physicians, patients, nurses and other non-clinical members of the study team were blinded for the first year of the study."
2414,PMC5529963,S45,['10'],"[0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,eighteen patients with ra were randomised into one of two treatment groups by a pharmacist who did not participate in the screening visit.
2415,PMC5529963,S46,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"eleven patients received infusions of infliximab at 5 mg/kg and seven received placebo (normal saline) infusions at weeks 0, 2 and 6, and then every 8 weeks through week 46."
2416,PMC5529963,S47,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"at the end of the first year, all patients were maintained a single-blinded study for a further year."
2417,PMC5529963,S48,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"patients in the methotrexate+infliximab (m+i ) group received infliximab infusions at weeks 54, 56, 62 and thereafter every 8 weeks."
2418,PMC5529963,S49,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,those in the m+i group received a placebo infusion at week 56 in order to maintain blinding and received infliximab infusions every 8 weeks until the end of the study (110 weeks) (see online supplementary appendix figure 1).
2419,PMC5529963,S50,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"as a result, all patients received a minimum of 1 year of infliximab in the two phases of the study."
2420,PMC5529963,S51,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,10.1136/heartjnl-2015-308953.supp1
2421,PMC5529963,S52,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,supplementary appendix 1
2422,PMC5529963,S53,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,baseline dosages of mtx or corticosteroid were maintained during the first 18 weeks of the study.
2423,PMC5529963,S54,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"after week 18, if any patient failed to achieve a 50% reduction from baseline in the number of swollen hand and wrist joints, the weekly dose of mtx was increased by 2.5 mg once every 4 weeks until a 50% reduction from baseline in the number of swollen hand and wrist joints was achieved, until the dosage of oral mtx reached 25 mg/week or until the dose escalation was limited by toxicity."
2424,PMC5529963,S55,['5'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"thereafter, irrespective of their response status, patients continued to receive the maximum tolerated mtx dosage until the end of the study."
2425,PMC5529963,S56,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"the study was approved by riverside research ethics committee, and all patients provided informed consent."
2426,PMC5529963,S57,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Study population and protocol,"clinical monitoring of the study was performed independently (centocor, malvern, pennsylvania, usa)."
2427,PMC5529963,S60,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,anthropometric measurements were made and body mass index (bmi (kg/m2)) was calculated from weight and height.
2428,PMC5529963,S61,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"blood pressure was measured in triplicate (hem-705cp, omron), and the average of the readings was calculated."
2429,PMC5529963,S62,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"blood was drawn and processed after an overnight fast, and serum and plasma samples were stored at −70°c for subsequent analysis."
2430,PMC5529963,S63,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"full blood count, lipid and glucose level measurements were made with standard biochemistry assays and c reactive protein (crp) was measured with an immunoturbidimetric, high-sensitivity assay (tina-quant assay performed on a cobas integra analyzer, roche diagnostics)."
2431,PMC5529963,S65,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"measurements of hdl function were carried out at baseline, 54 weeks and 110 weeks in patients with ra."
2432,PMC5529963,S66,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Laboratory assays,baseline measurements were compared with those from healthy controls.
2433,PMC5529963,S68,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,hdl was isolated by sequential ultracentrifugation (d=1.063–1.21 g/ml) using solid potassium bromide for density adjustment.8
2434,PMC5529963,S69,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,all functional assays of hdl were carried out within two weeks of isolation by a blinded investigator in duplicate.
2435,PMC5529963,S71,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"the effect of hdl (50 μg/ml: 60 min, 37°c) on endothelial nitric oxide (no) bioavailability (bovine aortic endothelial cells (baecs): passage 4–7; lonza bioscience) was measured using a fluorescent indicator."
2436,PMC5529963,S72,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"baecs were incubated with 4,5-diaminofluorescein diacetate (daf-2; 1um; cayman chemical), and triazolofluorescein fluorescence was measured using an excitation wavelength of 485 nm.9"
2437,PMC5529963,S74,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"the effect of hdl on endothelial cell superoxide production (so) was measured in unstimulated and tumour necrosis factor-α (tnf-α)-stimulated (5 ng/ml, r&d systems) human aortic endothelial cells (haecs) by erythrocyte sedimentation rate (esr) spectroscopy."
2438,PMC5529963,S75,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"haecs were incubated with hdl from patients and controls (50 μg/ml, 60 min, 37°c), with or without tnf-α and resuspended in krebs-hepes buffer (ph 7.4; noxygen) containing diethyldithiocarbamic acid sodium salt (5 μm, noxygen) and deferoxamine methanesulfonate salt (25 μm, noxygen)."
2439,PMC5529963,S76,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"esr spectra were recorded after addition of the spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (cmh; noxygen; final concentration 200 μm) using a bruker e-scan spectrometer (bruker biospin)."
2440,PMC5529963,S77,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,the esr instrumental settings were centre field (b0) 3495 g; field sweep width 10 g; microwave frequency 9.75 ghz; microwave power 19.91 mw; magnetic field modulation frequency 86.00 khz; modulation amplitude 2.60 g; conversion time 10.24 ms; and number of x-scans 1020.9
2441,PMC5529963,S79,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,hdl for measurements of efflux capacity was extracted from serum by apob depletion.
2442,PMC5529963,S80,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"whole serum was incubated for 20 min with a 20% polyethylene glycol (peg) solution (20% peg 8000 (sigma p2139) in 200 mm glycine (sigma g8898, ph=10))."
2443,PMC5529963,S81,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"samples were centrifuged at 1900 g, and the supernatant was collected and stored at 4°c."
2444,PMC5529963,S82,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,j774 cells were radiolabeled for 24 hours in a medium containing 2 μci of [3h]-cholesterol per microlitre.
2445,PMC5529963,S83,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,addition of 0.3 mm 8-(4-chlorophenylthio)-cyclic amp for 6 hours upregulated expression of abca1.
2446,PMC5529963,S84,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,an efflux medium containing 2.8% apolipoprotein b-depleted serum from each individual was added for 4 hours.
2447,PMC5529963,S85,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"to prevent cholesterol esterification during labelling, equilibration and flux, 2 μg/ml of cp113,818, a acyl-coenzyme a:cholesterol acyltransferase inhibitor was added to all mediums."
2448,PMC5529963,S86,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,efflux capacity was quantified using liquid scintillation to measure radioactive cholesterol effluxed from the cells (medium+intracellular lipids).
2449,PMC5529963,S87,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,all assays were performed in duplicate and the final average value normalised against a baseline control for statistical analyses between time points.10
2450,PMC5529963,S89,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"serum paraoxonase activities were measured by ultraviolet spectrophotometry in a 96-well plate format using paraoxon (sigma-aldrich, st louis, missouri, usa)."
2451,PMC5529963,S90,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"briefly, 50 μg/ml hdl was diluted in a reaction mixture containing 10 mm tris hydrochloride (ph 8.0), 1 m sodium chloride and 2 mm calcium chloride."
2452,PMC5529963,S91,['6a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0]",Laboratory assays,"at 24°c, 1.5 mm paraoxon was added to initiate the reaction, and the increase in absorbance at 405 nm was recorded over 30 min. an extinction coefficient (at 405 nm) of 17 000 m−1 • cm−1 was used to calculate units of paraoxonase-1 (pon-1).11"
2453,PMC5529963,S93,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistics,"hdl studies were powered for a 1:1 randomised controlled trial on the basis of no bioavailability using paired assessments in 35 healthy controls (mean=0.98, sd =0.13, and intraclass correlation 0.91).12"
2454,PMC5529963,S94,['7a'],"[0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0]",Statistics,"from this power calculation, a total of seven patients per group was required (power=80% and α=0.05) to detect a 5% difference in the primary outcome (no bioavailability)."
2455,PMC5529963,S95,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,normal distribution was assessed using the shapiro-wilk test.
2456,PMC5529963,S96,['0'],"[1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,all measures are reported as mean (sd) or median (iqr) for those not normally distributed.
2457,PMC5529963,S97,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,baseline comparisons were performed using an independent t-test or mann-whitney u test if data was non-normally distributed.
2458,PMC5529963,S98,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"post hoc multivariate analysis of variance (anova) modelling was performed to evaluate the effects of treatment with infliximab (vs placebo) and duration of treatment on hdl function, cv and clinical markers at 54 weeks."
2459,PMC5529963,S99,['12a'],"[0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0]",Statistics,"a repeated-measures anova, with time point comparisons using bonferroni-corrected t-tests, was performed to determine differences in hdl function, cv and clinical markers in patients who received 2 years infliximab treatment."