Context: Management of congenital hemophilia A and B is by prophylactic or on-demand replacement therapy with clotting factor concentrates. The effects of newer non-clotting factor therapies such as emicizumab, concizumab, marstacimab, and fitusiran compared with existing standards of care are yet to be systematically reviewed.

To assess the effects (clinical, economic, patient-reported, and adverse outcomes) of non-clotting factor therapies for preventing bleeding and bleeding-related complications in people with congenital hemophilia A or B compared with prophylaxis with clotting factor therapies, bypassing agents, placebo, or no prophylaxis.

Randomized controlled trials (RCTs) evaluating people with congenital hemophilia A or B with and without inhibitors, who were treated with non-clotting factor therapies to prevent bleeds.

Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model.

Abstract: Hemophilia is treated by IV replacement therapy with Factor VIII (FVIII) or Factor IX (FIX), either on demand to resolve bleeding, or as prophylaxis. Improved treatment may be provided by drugs designed for subcutaneous and less frequent administration with a reduced risk of inhibitor formation. Tissue factor pathway inhibitor (TFPI) down-regulates the initiation of coagulation by inhibition of Factor VIIa (FVIIa)/tissue factor/Factor Xa (FVIIa/TF/FXa). Blockage of TFPI inhibition may facilitate thrombin generation in a hemophilic setting. A high-affinity (K(D) = 25pM) mAb, mAb 2021, against TFPI was investigated. Binding of mAb 2021 to TFPI effectively prevented inhibition of FVIIa/TF/FXa and improved clot formation in hemophilia blood and plasma. The binding epitope on the Kunitz-type protease inhibitor domain 2 of TFPI was mapped by crystallography, and showed an extensive overlap with the FXa contact region highlighting a structural basis for its mechanism of action. In a rabbit hemophilia model, an intravenous or subcutaneous dose significantly reduced cuticle bleeding. mAb 2021 showed an effect comparable with that of rFVIIa. Cuticle bleeding in the model was reduced for at least 7 days by a single intravenous dose of mAb 2021. This study suggests that neutralization of TFPI by mAb 2021 may constitute a novel treatment option in hemophilia.

Pharmacokinetics of an anti-TFPI monoclonal antibody (concizumab) blocking the TFPI interaction with the active site of FXa in Cynomolgus monkeys after iv and sc administration.

Abstract:
Concizumab (mAb 2021) is a monoclonal IgG4 antibody (mAb) that binds to the Kunitz-type protease inhibitor (KPI) 2 domain of TFPI thereby blocking the interaction of this domain with the active site of FXa. The objective of the present study was to characterize the pharmacokinetics of concizumab in Cynomolgus monkeys after intravenous (iv) and subcutaneous (sc) administration.

Data from two studies were included in the modelling, all in all data from 52 monkeys distributed into 9 groups. Three groups received three escalating sc doses of concizumab with a one week dosing interval, two groups were administered a single dose, and four groups received multiple doses over 13 weeks of concizumab. The plasma concentration was measured using a standard ELISA, and pharmacokinetic data were analysed using NONMEM.

The pharmacokinetics of concizumab were characterised by a high bioavailability (93%) after sc administration. The time course of the elimination of concizumab from the circulation was well described by the proposed target mediated drug disposition (TMDD) model. The clearance of concizumab was estimated to be 0.14 ml/h/kg, the target clearance was characterized by a 50% saturation level of 0.54 μg/ml (Km), and the clearance at target saturation was estimated to be 11 μg/h/kg.

Concizumab displays a typical TMDD profile with important implications for a putative treatment regime in haemophilia patients. Compared to current standard haemophilia treatment, concizumab has a high bioavailability after sc administration and may provide a viable alternative to intravenous dosing for the treatment of haemophilia.

Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial.

Abstract:
Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia.

To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B.

In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 μg kg(-1) ) or s.c. (50-3000 μg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24).

Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h μg mL(-1) and a maximum mean concentration of 247 μg mL(-1) was measured at the highest dose.

Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.

A bispecific antibody mimicking factor VIII in hemophilia A therapy.

Abstract: Serious issues in current hemostatic treatment of hemophilia A are the requirement for frequent intravenous administrations of factor (F) VIII, FVIII inhibitor development, and hemostatic treatment for patients with this inhibitor. For the purpose of overcoming these challenges, the FVIIIa-substituting bispecific antibody against FIXa/FX (ACE910, INN emicizumab) was produced. Emicizumab demonstrated marked hemostatic effects on both ongoing and spontaneous joint bleeding in the acquired hemophilia A primate model. The clinical phase 1 study designed to assess the pharmacokinetics, pharmacodynamics and safety of emicizumab has been initiated. Severe emicizumab-related adverse events were minimal. The t1/2 was approximately 30 days, and bleeding events were significantly decreased by weekly subcutaneous administration in severe hemophilia A patients, independently of the presence of the inhibitor. Currently, the phase 1/2 extension study is ongoing. We anticipate that emicizumab will show the benefits of prophylactic efficacy with subcutaneous administration at a much lower frequency.

WFH 2016 World Congress Abstracts, Orlando, Florida, USA, July 24-28, 2016.

Abstracts of the 57th Annual Scientific Meeting of the British Society for Haematology, 27-29 March 2017, Brighton, UK.

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

Abstract:
Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.

In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran.

No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants.

Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors.

Abstract: Emicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII (FVIII) cofactor bridging function to restore hemostasis in people with hemophilia A. In a phase 1 trial involving 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous administration of emicizumab 0.3, 1, or 3 mg/kg (cohorts 1, 2, and 3, respectively) was well tolerated and substantially reduced annualized bleeding rates (ABRs) in the presence or absence of FVIII inhibitors. The current study represents an open-label, long-term extension of the previously reported 12-week phase 1 study, in which 16 of 18 patients continued to receive emicizumab for up to 33.3 months. Long-term emicizumab treatment was well tolerated, with no thromboembolic events reported and no neutralizing antiemicizumab antibodies developing during the course of the study. Plasma concentrations of emicizumab increased in a dose-proportional manner, with activated partial thromboplastin times remaining short. In cohorts 1, 2, and 3, respectively, median ABRs remained low at 1.4, 0.2, and 0 compared with 4.4, 0, and 0 in the 12-week study. Overall, 8 patients experienced no bleeding events (6 patients with and 2 patients without FVIII inhibitors); dose up-titration resulted in further reduction in ABRs in patients with suboptimal bleeding control; and the episodic use of clotting factors to control bleeding was reduced. In conclusion, long-term emicizumab treatment demonstrated a favorable safety profile with encouraging efficacy, irrespective of the presence of FVIII inhibitors, in patients with hemophilia A. This study was registered at www.clinicaltrials.jp as #JapicCTI-132195.


Context: Cystic fibrosis (CF) is a life-limiting genetic condition, affecting over 90,000 people worldwide. CF affects several organs in the body, but airway damage has the most profound impact on quality of life (QoL) and survival. Causes of lower airway infection in people with CF are, most notably, Staphylococcus aureus in the early course of the disease and Pseudomonas aeruginosa at a later stage. Macrolide antibiotics, e.g. azithromycin and clarithromycin, are usually taken orally, have a broad spectrum of action against gram-positive (e.g. S aureus) and some gram-negative bacteria (e.g. Haemophilus influenzae), and may have a modifying role in diseases involving airway infection and inflammation such as CF. They are well-tolerated and relatively inexpensive, but widespread use has resulted in the emergence of resistant bacteria. This is an updated review.

To assess the potential effects of macrolide antibiotics on clinical status in terms of benefit and harm in people with CF. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy.

We included randomised controlled trials of macrolide antibiotics in adults and children with CF. We compared them to: placebo; another class of antibiotic; another macrolide antibiotic; or the same macrolide antibiotic at a different dose or type of administration.

Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial.

Abstract:
Relentless chronic pulmonary inflammation is the major contributor to morbidity and mortality in patients with cystic fibrosis (CF). While immunomodulating therapies such as prednisolone and ibuprofen may be beneficial, their use is limited by side effects. Macrolides have immunomodulatory properties and long term use dramatically improves prognosis in diffuse panbronchiolitis, a condition with features in common with the lung disease of CF.

To determine if azithromycin (AZM) improves clinical parameters and reduces inflammation in patients with CF, a 3 month prospective randomised double blind, placebo controlled study of AZM (250 mg/day) was undertaken in adults with CF. Monthly assessment included lung function, weight, and quality of life (QOL). Blood and sputum collection assessed systemic inflammation and changes in bacterial flora. Respiratory exacerbations were treated according to the policy of the CF Unit.

Sixty patients were recruited (29 men) of mean (SD) age 27.9 (6.5) years and initial forced expiratory volume in 1 second (FEV1) 56.6 (22.3)% predicted. FEV1% and forced vital capacity (FVC)% predicted were maintained in the AZM group while in the placebo group there was a mean (SE) decline of -3.62 (1.78)% (p=0.047) and -5.73 (1.66)% (p=0.001), respectively. Fewer courses of intravenous antibiotics were used in patients on AZM (0.37 v 1.13, p=0.016). Median C reactive protein (CRP) levels declined in the AZM group from 10 to 5.4 mg/ml but remained constant in the placebo group (p<0.001). QOL improved over time in patients on AZM and remained unchanged in those on placebo (p=0.035).

AZM in adults with CF significantly improved QOL, reduced CRP levels and the number of respiratory exacerbations, and reduced the rate of decline in lung function. Long term AZM may have a significant impact on morbidity and mortality in patients with CF. Further studies are required to define frequency of dosing and duration of benefit.

Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial.

Abstract:
The macrolide antibiotic azithromycin has anti-inflammatory properties potentially beneficial in cystic fibrosis. Since findings of open pilot studies seemed to show clinical benefit, we undertook a formal trial.

41 children with cystic fibrosis, aged 8-18 years, and with a median forced expiratory volume in 1 s (FEV1) of 61% (range 33-80%) participated in a 15-month randomised double-blind, placebo-controlled crossover trial. They received either azithromycin (bodyweight < or =40 kg: 250 mg daily, >40 kg: 500 mg daily) or placebo for 6 months. After 2 months of washout, the treatments were crossed over. The primary outcome was median relative difference in FEV1 between azithromycin and placebo treatment periods. Sputum cultures, sputum interleukin 8 and neutrophil elastase, exercise testing, quality of life, antibiotic use, and pulmonary exacerbation rates were secondary outcome measures. Side-effects were assessed by pure tone audiometry and liver function tests. Analysis was by intention-to-treat.

Median relative difference in FEV1 between azithromycin and placebo was 5.4% (95% CI 0.8-10.5). 13 of 41 patients improved by more than 13% and five of 41 deteriorated by more than 13% (p=0.059). Forced vital capacity and mid-expiratory flow did not significantly change overall. 17 of 41 patients had 24 fewer oral antibiotic courses when on azithromycin than when taking placebo, and five had six extra courses (p=0.005). Sputum bacterial densities, inflammatory markers, exercise tolerance, and subjective well-being did not change. There were no noticeable side-effects.

A 4-6-month trial of azithromycin is justified in children with cystic fibrosis who do not respond to conventional treatment. The mechanism of action remains unknown.

Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.

Abstract:
Treatment strategies for cystic fibrosis (CF) lung disease include antibiotics, mucolytics, and anti-inflammatory therapies. Increasing evidence suggests that macrolide antibiotics might be beneficial in patients with CF.

To determine if an association between azithromycin use and pulmonary function exists in patients with CF.

A multicenter, randomized, double-blind, placebo-controlled trial conducted from December 15, 2000, to May 2, 2002, at 23 CF care centers in the United States.

Of the 251 screened participants with a diagnosis of CF, 185 (74%) were randomized. Eligibility criteria included age 6 years or older, infection with Pseudomonas aeruginosa for 1 or more years, and a forced expiratory volume in 1 second (FEV1) of 30% or more. Participants were stratified by FEV1 (> or =60% predicted vs <60% predicted), weight of less than 40 kg vs 40 kg or more, and CF center.

The active group (n = 87) received 250 mg (weight <40 kg) or 500 mg (weight > or =40 kg) of oral azithromycin 3 days a week for 168 days; placebo group (n = 98) received identically packaged tablets.

Change in FEV1 from day 0 to completion of therapy at day 168 and determination of safety. Secondary outcomes included pulmonary exacerbations and weight gain.

The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group (mean difference, 0.094 L; 95% confidence interval [CI], 0.023-0.165; P =.009). Nausea occurred in 17% more participants in the azithromycin group (P =.01), diarrhea in 15% more (P =.009), and wheezing in 13% more (P =.007). Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P =.03) and weighed at the end of the study an average 0.7 kg more than participants receiving placebo (95% CI, 0.1-1.4 kg; P =.02).

Azithromycin treatment was associated with improvement in clinically relevant end points and should be considered for patients with CF who are 6 years or older and chronically infected with P aeruginosa.

Effect of long-term treatment with azithromycin on disease parameters in cystic fibrosis.

Effect of clarithromycin on airway obstruction and inflammatory markers in induced sputum in cystic fibrosis: a pilot study.

Abstract: To determine whether macrolide antibiotics improve pulmonary function and decrease airway inflammation in cystic fibrosis (CF), we treated 10 patients (females; aged 19-26 years, all colonized with P. aeruginosa, none with atypical Mycobacteria) with 3 weeks of placebo, followed by 6 weeks of clarithromycin (500 mg BID) in a single-blind prospective study. We also determined the safety of sputum induction and the reproducibility of assessing inflammatory markers in induced sputum. Subjects performed spirometry and underwent sputum induction (12-min inhalation of 3% saline) at 3-week intervals. We found that sputum induction was well-tolerated. We also found that the reproducibility was high for neutrophil (PMN) number (R = 0.87, P = 0.009), interleukin (IL)-8 (R = 0.73, P < 0.05, free neutrophil elastase (NE) (R = 0.82, P < 0.05), and myeloperoxidase (MPO) levels (R = 0.86, P < 0.05), but was less so for tumor necrosis factor (TNF)-alpha (R = -0.15, P = 0.7). We found no significant difference in pulmonary function after 6 weeks of treatment with clarithromycin (FEV(1) (% predicted) (mean +/- SEM), 2.2 +/- 0.9 (60 +/- 24%) vs. 2.3 +/- 1 (61 +/- 29%)), and no significant differences in any of the inflammatory indices measured. The median (and range) values before and after treatment for indices of airway inflammation in the induced sputum samples were: for PMNs, 8 (1-326) and 21 (0.2 -175) x 10(6) cells/mL sputum; for IL-8, 156 (24-656) and 202 (16-680) ng/mL; for free NE, 260 (31-1,264) and 237 (49-1,048) microg/mL; for TNF-alpha, 20 (7-128) and 35 (17-87) pg/mL; and for MPO, 169 (13-960) and 195 (14-816) microg/mL. We conclude that clarithromycin is not uniformly effective in improving airway obstruction or in decreasing airway inflammation in patients with CF.

Long term azithromycin therapy in cystic fibrosis patients: a study on drug levels and sputum properties.

Abstract:
Following reports on the treatment of diffuse panbronchiolitis (DPB), recent studies demonstrate that long term therapy with azithromycin (AZM) is effective in cystic fibrosis (CF) patients. However, the underlying mechanisms remain uncertain. Some macrolides, including AZM, display inhibition of virulence factors and other antipseudomonal effects at subinhibitory levels in vitro.

Drug doses used for CF and DPB therapy were investigated to determine whether they achieve corresponding sputum drug levels in CF patients in vivo.

In an open, prospective study, 14 CF patients with chronic Pseudomonas aeruginosa airway infection received 250 mg AZM either daily ('high dose') or twice weekly ('low dose') for 12 weeks. Viscoelasticity of sputum was assessed by magnetic microrheology.

AZM accumulated in sputum by two orders of magnitude over a period of four weeks. In the following steady state, median AZM concentrations in sputum were 9.5 microg/mL (0.6 to 79.3 microg/mL, interquartiles 1.4 to 33.4 microg/mL) and 0.5 microg/mL (range less than 0.1 [below detection level] to 5.2 microg/mL, interquartiles 0.2 to 1.4 microg/mL) in the high and low dose groups, respectively. Viscoelasticity improved in all patients but one.

The findings suggest that antipseudomonal activity has to be considered among the potential mechanisms of macrolide therapy. Further, viscoelasticity may be a valuable parameter in future clinical trials.

Anti-inflammatory and immunomodulating effects of clarithromycin in patients with cystic fibrosis lung disease.

Abstract:
Macrolide antibiotics are widely used in the treatment of suppurative lung diseases including cystic fibrosis (CF), the most common inherited fatal disease in the Caucasian population. This condition is characterized by secondary Pseudomonas infection resulting in neutrophil infiltration within the airways. The aim of the study was to investigate the evolution of inflammatory process in CF patients receiving long-term clarithromycin therapy.

Twenty-seven CF patients (mean age, 12 years) were enrolled into the study. Beside the basic therapy the patients were treated with clarithromycin at a dose of 250 mg every other day orally. All patients were routinely examined every 3 months. Blood and sputum were collected before clarithromycin treatment and then again 3, 6 and 12 months after the drug prescription. Cytokine concentrations (tumor necrosis factor-alpha, interleukin-8, interleukin-4, interferon-gamma) in the sputum and plasma were assayed. Peripheral blood lymphocyte response to phytohemagglutinin was also evaluated.

Clarithromycin treatment resulted in a marked reduction of the cytokine levels both in the sputum and plasma specimens. At the same time, the interferon-gamma/interleukin-4 ratio has been significantly elevated. In addition, a sustained increase of peripheral blood lymphocyte response to phytohemagglutinin was demonstrated. These changes were associated with a significant improvement of the lung function.

The beneficial effect of the prolonged treatment of CF patients with a 14-membered ring macrolide antibiotic clarithromycin seems to be associated not only with down-regulation of the inflammatory response, but also with immunological changes including the switch from Th2 to Th1 type response.

Effect of macrolides on in vivo ion transport across cystic fibrosis nasal epithelium.

Abstract: Fourteen- and 15-member macrolide antibiotics are under investigation as potential therapeutic agents for cystic fibrosis (CF). The nonantibiotic mechanisms of action of these compounds in CF are not understood. We used nasal potential difference (NPD) measurements to test the effect of macrolides on airway epithelial ion (chloride, sodium) transport of CF mice and humans. We tested clarithromycin and azithromycin in mice, and clarithromycin in patients with CF. Baseline and post-treatment NPD was measured in two strains (C57Bl6 and BalbC) of CF transmembrane regulator "knockout" and littermate control mice, and in DeltaF508/DeltaF508 mice. In addition, NPD was measured in 18 human subjects with CF (17 DeltaF-508/DeltaF-508 and 1 DeltaF-508/other) who were undergoing a 12-month, randomized, double-blind crossover study of the effects of clarithromycin on pulmonary outcome in CF. Neither clarithromycin nor azithromycin affected ion transport characteristics of normal or CF nasal epithelium in either mouse or humans. We conclude that the apparent beneficial effects of macrolides on pulmonary outcome in CF are not mediated by their modulation of ion transport.

Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial.

Abstract:
We did a randomised, double-blind, controlled clinical trial to prospectively assess whether use of combination antibiotic susceptibility testing improved clinical outcomes in patients with acute pulmonary exacerbations of cystic fibrosis who were infected with multiresistant bacteria.

251 patients with cystic fibrosis who were chronically infected with multiresistant gram negative bacteria gave sputum at 3-month intervals for conventional culture and sensitivity tests and for combination antibiotic susceptibility tests using multiple combination bactericidal antibiotic testing (MCBT). Patients who developed an exacerbation of pulmonary disease were randomised to receive a 14-day course of any two blinded intravenous antibiotics chosen on the basis of either results from conventional sputum culture and sensitivity testing or the result of MCBT. The primary outcome was time from randomisation until the patient's next pulmonary exacerbation. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN60187870.

132 patients had a pulmonary exacerbation and were randomised during the 4.5-year study period. The time to next pulmonary exacerbation was not prolonged in the MCBT-treated group (hazard ratio 0.86 in favour of the conventionally-treated group, 95% CI 0.60-1.23, p=0.40). There was no difference between the groups in treatment failure rate. After 14 days of intravenous antibiotic therapy, changes in lung function, dyspnoea, and sputum bacterial density were similar in both groups.

Antibiotic therapy directed by combination antibiotic susceptibility testing did not result in better clinical and bacteriological outcomes compared with therapy directed by standard culture and sensitivity techniques. The non-bactericidal effects of antibiotic therapy might play an important part in determining improvement in patients with cystic fibrosis pulmonary exacerbations.


Context: Obesity is considered to be a risk factor for various diseases, and its incidence has tripled worldwide since 1975. In addition to potentially being at risk for adverse health outcomes, people with overweight or obesity are often stigmatised. Behaviour change interventions are increasingly delivered as mobile health (m-health) interventions, using smartphone apps and wearables. They are believed to support healthy behaviours at the individual level in a low-threshold manner.

To assess the effects of integrated smartphone applications for adolescents and adults with overweight or obesity.

Participants were adolescents and adults with overweight or obesity. Eligible interventions were integrated smartphone apps using at least two behaviour change techniques. The intervention could target physical activity, cardiorespiratory fitness, weight loss, healthy diet, or self-efficacy. Comparators included no or minimal intervention (NMI), a different smartphone app, personal coaching, or usual care. Eligible studies were randomised controlled trials of any duration with a follow-up of at least three months.

Adherence to a smartphone application for weight loss compared to website and paper diary: pilot randomized controlled trial.

Abstract:
There is growing interest in the use of information communication technologies to treat obesity. An intervention delivered by smartphone could be a convenient, potentially cost-effective, and wide-reaching weight management strategy. Although there have been studies of texting-based interventions and smartphone applications (apps) used as adjuncts to other treatments, there are currently no randomized controlled trials (RCT) of a stand-alone smartphone application for weight loss that focuses primarily on self-monitoring of diet and physical activity.

The aim of this pilot study was to collect acceptability and feasibility outcomes of a self-monitoring weight management intervention delivered by a smartphone app, compared to a website and paper diary.

A sample of 128 overweight volunteers were randomized to receive a weight management intervention delivered by smartphone app, website, or paper diary. The smartphone app intervention, My Meal Mate (MMM), was developed by the research team using an evidence-based behavioral approach. The app incorporates goal setting, self-monitoring of diet and activity, and feedback via weekly text message. The website group used an existing commercially available slimming website from a company called Weight Loss Resources who also provided the paper diaries. The comparator groups delivered a similar self-monitoring intervention to the app, but by different modes of delivery. Participants were recruited by email, intranet, newsletters, and posters from large local employers. Trial duration was 6 months. The intervention and comparator groups were self-directed with no ongoing human input from the research team. The only face-to-face components were at baseline enrollment and brief follow-up sessions at 6 weeks and 6 months to take anthropometric measures and administer questionnaires.

Trial retention was 40/43 (93%) in the smartphone group, 19/42 (55%) in the website group, and 20/43 (53%) in the diary group at 6 months. Adherence was statistically significantly higher in the smartphone group with a mean of 92 days (SD 67) of dietary recording compared with 35 days (SD 44) in the website group and 29 days (SD 39) in the diary group (P<.001). Self-monitoring declined over time in all groups. In an intention-to-treat analysis using baseline observation carried forward for missing data, mean weight change at 6 months was -4.6 kg (95% CI -6.2 to -3.0) in the smartphone app group, -2.9 kg (95% CI -4.7 to -1.1) in the diary group, and -1.3 kg (95% CI -2.7 to 0.1) in the website group. BMI change at 6 months was -1.6 kg/m(2) (95% CI -2.2 to -1.1) in the smartphone group, -1.0 kg/m(2) (95% CI -1.6 to -0.4) in the diary group, and -0.5 kg/m(2) (95% CI -0.9 to 0.0) in the website group. Change in body fat was -1.3% (95% CI -1.7 to -0.8) in the smartphone group, -0.9% (95% CI -1.5 to -0.4) in the diary group, and -0.5% (95% CI -0.9 to 0.0) in the website group.

The MMM app is an acceptable and feasible weight loss intervention and a full RCT of this approach is warranted.

ClinicalTrials.gov NCT01744535; http://clinicaltrials.gov/ct2/show/NCT01744535 (Archived by WebCite at http://www.webcitation.org/6FEtc3PVB).

Weight loss intervention for young adults using mobile technology: design and rationale of a randomized controlled trial - Cell Phone Intervention for You (CITY).

Abstract:
The obesity epidemic has spread to young adults, leading to significant public health implications later in adulthood. Intervention in early adulthood may be an effective public health strategy for reducing the long-term health impact of the epidemic. Few weight loss trials have been conducted in young adults. It is unclear what weight loss strategies are beneficial in this population.

To describe the design and rationale of the NHLBI-sponsored Cell Phone Intervention for You (CITY) study, which is a single center, randomized three-arm trial that compares the impact on weight loss of 1) a behavioral intervention that is delivered almost entirely via cell phone technology (Cell Phone group); and 2) a behavioral intervention delivered mainly through monthly personal coaching calls enhanced by self-monitoring via cell phone (Personal Coaching group), each compared to 3) a usual care, advice-only control condition.

A total of 365 community-dwelling overweight/obese adults aged 18-35 years were randomized to receive one of these three interventions for 24 months in parallel group design. Study personnel assessing outcomes were blinded to group assignment. The primary outcome is weight change at 24 [corrected] months. We hypothesize that each active intervention will cause more weight loss than the usual care condition. Study completion is anticipated in 2014.

If effective, implementation of the CITY interventions could mitigate the alarming rates of obesity in young adults through promotion of weight loss. ClinicalTrial.gov: NCT01092364.

Adaptive intervention design in mobile health: Intervention design and development in the Cell Phone Intervention for You trial.

Abstract:
The obesity epidemic has spread to young adults, and obesity is a significant risk factor for cardiovascular disease. The prominence and increasing functionality of mobile phones may provide an opportunity to deliver longitudinal and scalable weight management interventions in young adults. The aim of this article is to describe the design and development of the intervention tested in the Cell Phone Intervention for You study and to highlight the importance of adaptive intervention design that made it possible. The Cell Phone Intervention for You study was a National Heart, Lung, and Blood Institute-sponsored, controlled, 24-month randomized clinical trial comparing two active interventions to a usual-care control group. Participants were 365 overweight or obese (body mass index≥25 kg/m2) young adults.

Both active interventions were designed based on social cognitive theory and incorporated techniques for behavioral self-management and motivational enhancement. Initial intervention development occurred during a 1-year formative phase utilizing focus groups and iterative, participatory design. During the intervention testing, adaptive intervention design, where an intervention is updated or extended throughout a trial while assuring the delivery of exactly the same intervention to each cohort, was employed. The adaptive intervention design strategy distributed technical work and allowed introduction of novel components in phases intended to help promote and sustain participant engagement. Adaptive intervention design was made possible by exploiting the mobile phone's remote data capabilities so that adoption of particular application components could be continuously monitored and components subsequently added or updated remotely.

The cell phone intervention was delivered almost entirely via cell phone and was always-present, proactive, and interactive-providing passive and active reminders, frequent opportunities for knowledge dissemination, and multiple tools for self-tracking and receiving tailored feedback. The intervention changed over 2 years to promote and sustain engagement. The personal coaching intervention, alternatively, was primarily personal coaching with trained coaches based on a proven intervention, enhanced with a mobile application, but where all interactions with the technology were participant-initiated.

The complexity and length of the technology-based randomized clinical trial created challenges in engagement and technology adaptation, which were generally discovered using novel remote monitoring technology and addressed using the adaptive intervention design. Investigators should plan to develop tools and procedures that explicitly support continuous remote monitoring of interventions to support adaptive intervention design in long-term, technology-based studies, as well as developing the interventions themselves.

Cell phone intervention for you (CITY): A randomized, controlled trial of behavioral weight loss intervention for young adults using mobile technology.

Abstract:
To determine the effect on weight of two mobile technology-based (mHealth) behavioral weight loss interventions in young adults.

Randomized, controlled comparative effectiveness trial in 18- to 35-year-olds with BMI ≥ 25 kg/m(2) (overweight/obese), with participants randomized to 24 months of mHealth intervention delivered by interactive smartphone application on a cell phone (CP); personal coaching enhanced by smartphone self-monitoring (PC); or Control.

The 365 randomized participants had mean baseline BMI of 35 kg/m(2) . Final weight was measured in 86% of participants. CP was not superior to Control at any measurement point. PC participants lost significantly more weight than Controls at 6 months (net effect -1.92 kg [CI -3.17, -0.67], P = 0.003), but not at 12 and 24 months.

Despite high intervention engagement and study retention, the inclusion of behavioral principles and tools in both interventions, and weight loss in all treatment groups, CP did not lead to weight loss, and PC did not lead to sustained weight loss relative to Control. Although mHealth solutions offer broad dissemination and scalability, the CITY results sound a cautionary note concerning intervention delivery by mobile applications. Effective intervention may require the efficiency of mobile technology, the social support and human interaction of personal coaching, and an adaptive approach to intervention design.

Smartphone Technology and Text Messaging for Weight Loss in Young Adults: A Randomized Controlled Trial.

Abstract:
Using smartphone technology and text messaging for health is a growing field. This type of technology is well integrated into the lives of young adults. However, few studies have tested the effect of this type of technology to promote weight loss in young adults OBJECTIVE:: The purpose of this study is to test the effectiveness of a behaviorally based smartphone application for weight loss combined with text messaging from a health coach on weight, body mass index (BMI), and waist circumference in young adults as compared with a control condition.

Sixty-two young adults, aged 18 to 25 years, were randomized to receive (1) a smartphone application + health coach intervention and counseling sessions or (2) control condition with a counseling session. All outcome measures were tested at baseline and 3 months. These included weight, BMI, waist circumference, dietary habits, physical activity habits, and self-efficacy for healthy eating and physical activity.

The sample was 71% female and 39% white, with an average age of 20 years and average BMI of 28.5 kg/m. Participants in the smartphone + health coach group lost significantly more weight (P = .026) and had a significant reduction in both BMI (P = .024) and waist circumference (P < .01) compared with controls.

The results of this weight loss trial support the use of smartphone technology and feedback from a health coach on improving weight in a group of diverse young adults.

Tweets, Apps, and Pods: Results of the 6-month Mobile Pounds Off Digitally (Mobile POD) randomized weight-loss intervention among adults.

Abstract:
Previous interventions have shown promising results using theory-based podcasts to deliver a behavioral weight-loss intervention.

The objective of our study was to examine whether a combination of podcasting, mobile support communication, and mobile diet monitoring can assist people in weight loss.

In this 6-month, minimal contact intervention, overweight (n = 96, body mass index 32.6 kg/m(2)) adults were recruited through television advertisements and email listservs and randomly assigned to Podcast-only or Podcast+Mobile groups. Both groups received 2 podcasts per week for 3 months and 2 minipodcasts per week for months 3-6. In addition to the podcasts, the Podcast+Mobile group was also instructed to use a diet and physical activity monitoring application (app) on their mobile device and to interact with study counselors and other participants on Twitter.

Weight loss did not differ by group at 6 months: mean -2.7% (SD 5.6%) Podcast+Mobile, n = 47; mean -2.7% (SD 5.1%) Podcast, n = 49; P = .98. Days/week of reported diet monitoring did not differ between Podcast+Mobile (mean 2.3, SD 1.9 days/week) and Podcast groups (mean 1.9, SD 1.7 days/week; P = .28) but method of monitoring did differ. Podcast+Mobile participants were 3.5 times more likely than the Podcast group to use an app to monitor diet (P = .01), whereas the majority of Podcast participants reported using the Web (14/41, 34%) or paper (12/41, 29%). There were more downloads per episode in the Podcast+Mobile group (1.4/person) than in the Podcast group (1.1/person; P < .001). The number of podcasts participants reported downloading over the 6-month period was significantly moderately correlated with weight loss in both the Podcast+Mobile (r = -.46, P = .001) and the Podcast (r = -.53, P < .001) groups. Podcast+Mobile participants felt more user control at 3 months (P = .02), but not at 6 months, and there was a trend (P = .06) toward greater elaboration among Podcast+Mobile participants. There were significant differences in reported source of social support between groups. More Podcast participants relied on friends (11/40, 28% vs 4/40, 10%; P = .045) whereas Podcast+Mobile participants relied on online sources (10/40, 25% vs 0/40; P = .001).

Results confirm and extend previous findings showing a minimally intensive weight-loss intervention can be delivered via podcast, but prompting and mobile communication via Twitter and monitoring app without feedback did not enhance weight loss.

Clinicaltrials.gov NCT01139255; http://clinicaltrials.gov/ct2/show/NCT01139255 (Archived by WebCite at http://www.webcitation.org/625OjhiDy).

A smartphone-supported weight loss program: design of the ENGAGED randomized controlled trial.

Abstract:
Obesity remains a major public health challenge, demanding cost-effective and scalable weight management programs. Delivering key treatment components via mobile technology offers a potential way to reduce expensive in-person contact, thereby lowering the cost and burden of intensive weight loss programs. The ENGAGED study is a theory-guided, randomized controlled trial designed to examine the feasibility and efficacy of an abbreviated smartphone-supported weight loss program.

Ninety-six obese adults (BMI 30-39.9 kg/m2) will be randomized to one of three treatment conditions: (1) standard behavioral weight loss (STND), (2) technology-supported behavioral weight loss (TECH); or (3) self-guided behavioral weight loss (SELF). All groups will aim to achieve a 7% weight loss goal by reducing calorie and fat intake and progressively increasing moderate intensity physical activity to 175 minutes/week. STND and TECH will attend 8 group sessions and receive regular coaching calls during the first 6 months of the intervention; SELF will receive the Group Lifestyle Balance Program DVD's and will not receive coaching calls. During months 1-6, TECH will use a specially designed smartphone application to monitor dietary intake, body weight, and objectively measured physical activity (obtained from a Blue-tooth enabled accelerometer). STND and SELF will self-monitor on paper diaries. Linear mixed modeling will be used to examine group differences on weight loss at months 3, 6, and 12. Self-monitoring adherence and diet and activity goal attainment will be tested as mediators.

ENGAGED is an innovative weight loss intervention that integrates theory with emerging mobile technologies. We hypothesize that TECH, as compared to STND and SELF, will result in greater weight loss by virtue of improved behavioral adherence and goal achievement.

NCT01051713.


Context: Infliximab is a monoclonal antibody that binds and neutralises tumour necrosis factor-alpha (TNF-α) which is present in high levels in the blood serum, mucosa and stool of patients with Crohn's disease.

To determine the efficacy and safety of infliximab for maintaining remission in patients with Crohn's disease.

Randomised controlled trials (RCTs) in which infliximab was compared to placebo or another active comparator for maintenance, remission, or response in patients with Crohn's disease.

Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.

Abstract:
Infliximab, an anti-tumor necrosis factor monoclonal antibody, rapidly reduces signs and symptoms of active Crohn's disease. The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit.

The efficacy, safety, pharmacokinetics, and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a randomized, double-blind, placebo-controlled, parallel group trial. Seventy-three patients with active Crohn's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response (>/=70-point decrease in the Crohn's Disease Activity Index) to an initial infusion of infliximab (or placebo) were studied.

Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab. Median values for Crohn's Disease Activity Index, inflammatory bowel disease questionnaire (a quality of life measurement), and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment, but not with placebo retreatment. Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity. One case of lymphoma and 1 case of suspected lupus were reported; the complete long-term safety profile of infliximab requires additional clinical investigation.

Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn's disease not responding to conventional treatments.

Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.

Abstract:
We did a randomised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn's disease who respond to a single infusion of infliximab.

573 patients with a score of at least 220 on the Crohn's disease activity index (CDAI) received a 5 mg/kg intravenous infusion of infliximab at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg (group III). The prespecified co-primary endpoints were the proportion of patients who responded at week 2 and were in remission (CDAI <150) at week 30 and the time to loss of response up to week 54 in patients who responded. Analyses of the co-primary endpoints were by intention to treat.

335 (58%) patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 of 110 (21%) group I patients were in remission, compared with 44 of 113 (39%) group II (p=0.003) and 50 of 112 (45%) group III (p=0.0002) patients. Thus, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio 2.7, 95% CI 1.6-4.6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (IQR 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10-45) for group I (p=0.002 and p=0.0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohn's disease and rheumatoid arthritis. In particular, the incidence of serious infections was similar across treatment groups.

Patients with Crohn's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks.

The effects of infliximab maintenance therapy on health-related quality of life.

Abstract:
The ACCENT I study evaluated the long term effects of infliximab as maintenance therapy for patients with Crohn's disease. Health-related quality of life (HRQL) was also assessed in the trial.

In ACCENT I, a total of 573 patients received a single infusion of 5 mg/kg infliximab at baseline. After assessment of response at wk 2, patients were randomly assigned repeat infusions of placebo at wk 2 and 6 and then every 8 wk thereafter until wk 46 (single dose), repeat infusions of 5 mg/kg of infliximab at the same time points (5 mg/kg maintenance), or 5 mg/kg of infliximab at wk 2 and 6 followed by 10 mg/kg (10 mg/kg maintenance). HRQL analyses presented include the 335 patients classified as wk-2 responders. The treatment regimens were compared with regard to their change from baseline in the IBDQ and Short Form-36 (SF-36) scores.

Baseline scores indicated substantial impairment in HRQL. Throughout the study, all IBDQ and SF-36 scores were improved at all time points compared to baseline. After wk 10 and through wk 54, these improvements were greater in the two infliximab maintenance groups than in the single-dose group. The mean change from baseline to wk 54 in total IBDQ was greater in the 5-mg/kg maintenance group (22.1, p < 0.05) and 10-mg/kg maintenance group (30.2, p < 0.001) than in the single-dose group (8.9). Similarly, the mean change from baseline to wk 54 in the PCS of the SF-36 was greater in the 5-mg/kg maintenance group (6.1, p < 0.05) and 10-mg/kg maintenance group (7.2, p < 0.01) than in the single-dose group (2.5).

Infliximab therapy provides substantially improved HRQL as measured by both the disease-specific IBDQ and the generic SF-36. A maintenance regimen of either 5 mg/kg or 10 mg/kg of infliximab is more effective than a single 5-mg/kg infliximab infusion in sustaining this benefit.

Infliximab for the treatment of fistulas in patients with Crohn's disease.

Abstract:
Enterocutaneous fistulas are a serious complication of Crohn's disease and are difficult to treat. Infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, has recently been developed as a treatment for Crohn's disease. We conducted a randomized, multicenter, double-blind, placebo-controlled trial of infliximab for the treatment of fistulas in patients with Crohn's disease.

The study included 94 adult patients who had draining abdominal or perianal fistulas of at least three months' duration as a complication of Crohn's disease. Patients were randomly assigned to receive one of three treatments: placebo (31 patients), 5 mg of infliximab per kilogram of body weight (31 patients), or 10 mg of infliximab per kilogram (32 patients); all three were to be administered intravenously at weeks 0, 2, and 6. The primary end point was a reduction of 50 percent or more from base line in the number of draining fistulas observed at two or more consecutive study visits. A secondary end point was the closure of all fistulas.

Sixty-eight percent of the patients who received 5 mg of infliximab per kilogram and 56 percent of those who received 10 mg per kilogram achieved the primary end point, as compared with 26 percent of the patients in the placebo group (P=0.002 and P=0.02, respectively). In addition, 55 percent of the patients assigned to receive 5 mg of infliximab per kilogram and 38 percent of those assigned to 10 mg per kilogram had closure of all fistulas, as compared with 13 percent of the patients assigned to placebo (P=0.001 and P=0.04, respectively). The median length of time during which the fistulas remained closed was three months. More than 60 percent of patients in all the groups had adverse events. For patients treated with infliximab, the most common were headache, abscess, upper respiratory tract infection, and fatigue.

Infliximab is an efficacious treatment for fistulas in patients with Crohn's disease.

Infliximab (REMICADE) therapy in the treatment of pediatric Crohn's disease.

Abstract:
The aim of this study was to assess the efficacy and safety of a single infusion of infliximab in the treatment of pediatric Crohn's disease (CD).

A total of 21 pediatric CD patients were enrolled at seven study centers and randomized to receive a single infusion of infliximab 1 mg/kg (n = 6), 5 mg/kg (n = 7), or 10 mg/kg (n = 8) over at least 2 hrs at week 0 in this multicenter, open-label, dose-blinded trial. Efficacy assessments, including the Pediatric Crohn's Disease Activity Index (PCDAI), modified CDAI, C-reactive protein concentration (CRP), and erythrocyte sedimentation rate (ESR) determinations, were made at screening and at weeks 1, 2, 4, 8, and 12. Adverse events were assessed throughout study participation.

Improvements in the PCDAI, modified CDAI, ESR, and CRP were observed with all infliximab doses, beginning at week 1. On average, all treated patients experienced approximately 50% improvement in the PCDAI by week 2. By week 12, the PCDAI remained approximately 30% improved from baseline. During the study, all 21 patients (100%) achieved a clinical response, and 10 patients (48%) achieved clinical remission. There were no infusion reactions in any of the treatment arms.

The results of this trial suggest that infliximab may be safe and effective as short-term therapy of medically refractory moderate to severe CD in a pediatric population.

Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children.

Abstract:
The REACH study evaluated the safety and efficacy of infliximab in children with moderately to severely active Crohn's disease.

Patients (n = 112) with a Pediatric Crohn's Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6. Patients responding to treatment at week 10 were randomized to infliximab 5 mg/kg every 8 or 12 weeks through week 46. A concurrent immunomodulator was required. Clinical response (decrease from baseline in the PCDAI score > or =15 points; total score < or =30) and clinical remission (PCDAI score < or =10 points) were evaluated at weeks 10, 30, and 54.

At week 10, 99 of 112 (88.4%) patients responded to infliximab (95% confidence interval: [82.5%, 94.3%]) and 66 of 112 (58.9%) patients achieved clinical remission (95% confidence interval: [49.8%, 68.0%]). At week 54, 33 of 52 (63.5%) and 29 of 52 (55.8%) patients receiving infliximab every 8 weeks did not require dose adjustment and were in clinical response and clinical remission, respectively, compared with 17 of 51 (33.3%) and 12 of 51 (23.5%) patients receiving treatment every 12 weeks (P = .002 and P < .001, respectively).

Pediatric patients responding to an induction regimen of infliximab were more likely to be in clinical response and remission at week 54 without dose adjustment when their maintenance therapy was given every 8 weeks rather than every 12 weeks. Allowing for dose intensification in the case of relapse, remission rates, but not response rates, at week 54 were superior with every 8-week dosing compared with every 12-week dosing.

Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial.

Abstract:
Most patients who have active Crohn's disease are treated initially with corticosteroids. Although this approach usually controls symptoms, many patients become resistant to or dependent on corticosteroids, and long exposure is associated with an increased risk of mortality. We aimed to compare the effectiveness of early use of combined immunosuppression with conventional management in patients with active Crohn's disease who had not previously received glucocorticoids, antimetabolites, or infliximab.

We did a 2-year open-label randomised trial at 18 centres in Belgium, Holland, and Germany between May, 2001, and January, 2004. We randomly assigned 133 patients to either early combined immunosuppression or conventional treatment. The 67 patients assigned to combined immunosuppression received three infusions of infliximab (5 mg/kg of bodyweight) at weeks 0, 2, and 6, with azathioprine. We gave additional treatment with infliximab and, if necessary, corticosteroids, to control disease activity. 66 patients assigned to conventional management received corticosteroids, followed, in sequence, by azathioprine and infliximab. The primary outcome measures were remission without corticosteroids and without bowel resection at weeks 26 and 52. Analysis was by modified intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00554710.

Four patients (two in each group) did not receive treatment as per protocol. At week 26, 39 (60.0%) of 65 patients in the combined immunosuppression group were in remission without corticosteroids and without surgical resection, compared with 23 (35.9%) of 64 controls, for an absolute difference of 24.1% (95% CI 7.3-40.8, p=0.0062). Corresponding rates at week 52 were 40/65 (61.5%) and 27/64 (42.2%) (absolute difference 19.3%, 95% CI 2.4-36.3, p=0.0278). 20 of the 65 patients (30.8%) in the early combined immunosuppression group had serious adverse events, compared with 19 of 64 (25.3%) controls (p=1.0).

Combined immunosuppression was more effective than conventional management for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohn's disease. Initiation of more intensive treatment early in the course of the disease could result in better outcomes.

[Maintenance treatment by anti-tumor necrosis factor monoclonal antibody in Crohn's disease--long-term effects and safety].

Efficacy of infliximab in pediatric Crohn's disease: a randomized multicenter open-label trial comparing scheduled to on demand maintenance therapy.

Abstract:
Infliximab (IFX) is efficacious in inducing remission in severe forms of pediatric Crohn's disease (CD). Adult studies indicate that IFX is also safe and well tolerated as maintenance therapy. The present study aimed to evaluate in a prospective manner the efficacy and safety of IFX as maintenance therapy of severe pediatric CD comparing scheduled and "on demand" treatment strategies.

Forty children with CD (nonpenetrating, nonstricturing as well as penetrating forms, mean age: 13.9 +/- 2.2 years) with a severe flare-up (Harvey-Bradshaw Index [HBI] > or =5, erythrocyte sedimentation rate [ESR] >20 mm/h) despite well-conducted immunomodulator therapy (n = 36 azathioprine, n = 1 mercaptopurine, n = 3 methotrexate) combined with steroids were included in this randomized, multicenter, open-label study. Three IFX infusions (5 mg/kg) were administered at week (W)0/W2/W6. At W10, clinical remission (HBI <5) and steroid withdrawal were analyzed and IFX responders were randomized to maintenance therapy over 1 year: group A, scheduled every 2 months; group B, "on demand" on relapse.

In all, 34/40 children came into remission during IFX induction therapy (HBI: 6.7 +/- 2.5 (WO) vs. 1.1 +/- 1.5 (W10); P < 0.001). At the end of phase 2, 15/18 (83%) patients were in remission in group A compared to 8/13 (61%) children in group B (P < 0.01), with a mean HBI of 0.5 versus 3.2 points (group A versus B, P = 0.011). In group A, 3/13 (23.1%) children experienced a relapse compared to 11/12 (92%) children in group B. No severe adverse event occurred during this trial.

IFX is well tolerated and safe as maintenance therapy for pediatric CD, with a clear advantage when used on a scheduled 2-month basis compared to an "on demand" basis.

Infliximab prevents Crohn's disease recurrence after ileal resection.

Abstract:
Crohn's disease commonly recurs after intestinal resection. We evaluated whether the administration of infliximab after resective intestinal surgery for Crohn's disease reduces postoperative recurrence.

We randomly assigned 24 patients with Crohn's disease who had undergone ileocolonic resection to receive intravenous infliximab (5 mg/kg), administered within 4 weeks of surgery and continued for 1 year, or placebo. The primary end point was the proportion of patients with endoscopic recurrence at 1 year. Secondary end points were clinical recurrence and remission and histologic recurrence.

The rate of endoscopic recurrence at 1 year was significantly lower in the infliximab group (1 of 11 patients; 9.1%) compared with the placebo group (11 of 13 patients; 84.6%) (P = .0006). There was a nonsignificant higher proportion of patients in clinical remission in the infliximab group (8 of 10; 80.0%) compared with the placebo group (7 of 13; 53.8%) (P = .38). The histologic recurrence rate at 1 year was significantly lower in the infliximab group (3 of 11 patients; 27.3%) compared with the placebo group (11 of 13 patients; 84.6%) (P = .01). The occurrence of adverse events was similar between the placebo and infliximab groups, and none occurred in the immediate postoperative period.

Administration of infliximab after intestinal resective surgery was effective at preventing endoscopic and histologic recurrence of Crohn's disease.


Context: Interventions incorporating meditation to address stress, anxiety, and depression, and improve self-management, are becoming popular for many health conditions. Stress is a risk factor for cardiovascular disease (CVD) and clusters with other modifiable behavioural risk factors, such as smoking. Meditation may therefore be a useful CVD prevention strategy.

To determine the effectiveness of meditation, primarily mindfulness-based interventions (MBIs) and transcendental meditation (TM), for the primary and secondary prevention of CVD.

We included randomised controlled trials (RCTs) of 12 weeks or more in adults at high risk of CVD and those with established CVD. We explored four comparisons: MBIs versus active comparators (alternative interventions); MBIs versus non-active comparators (no intervention, wait list, usual care); TM versus active comparators; TM versus non-active comparators.

Effects of stress reduction on carotid atherosclerosis in hypertensive African Americans.

Abstract:
African Americans suffer disproportionately higher cardiovascular disease mortality rates than do whites. Psychosocial stress influences the development and progression of atherosclerosis. Carotid intima-media thickness (IMT) is a valid surrogate measure for coronary atherosclerosis, is a predictor of coronary outcomes and stroke, and is associated with psychosocial stress factors. Stress reduction with the Transcendental Meditation (TM) program decreases coronary heart disease risk factors and cardiovascular mortality in African Americans. B-mode ultrasound is useful for the noninvasive evaluation of carotid atherosclerosis.

This randomized controlled clinical trial evaluated the effects of the TM program on carotid IMT in hypertensive African American men and women, aged >20 years, over a 6- to 9-month period. From the initially enrolled 138 volunteers, 60 subjects completed pretest and posttest carotid IMT data. The assigned interventions were either the TM program or a health education group. By use of B-mode ultrasound, mean maximum IMT from 6 carotid segments was used to determine pretest and posttest IMT values. Regression analysis and ANCOVA were performed.

Age and pretest IMT were found to be predictors of posttest IMT values and were used as covariates. The TM group showed a significant decrease of -0.098 mm (95% CI -0. 198 to 0.003 mm) compared with an increase of 0.054 mm (95% CI -0.05 to 0.158 mm) in the control group (P=0.038, 2-tailed).

Stress reduction with the TM program is associated with reduced carotid atherosclerosis compared with health education in hypertensive African Americans. Further research with this stress-reduction technique is warranted to confirm these preliminary findings.

Behavioral treatment of hypertensive heart disease in African Americans: rationale and design of a randomized controlled trial.

Abstract: African Americans experience higher morbidity and mortality than Whites do as a result of hypertension and associated cardiovascular disease. Chronic psychosocial stress has been considered an important contributing factor to these high rates. The authors describe the rationale and design for a planned randomized controlled trial comparing Transcendental Meditation, a stress-reduction technique, with lifestyle education in the treatment of hypertension and hypertensive heart disease in urban African Americans. They pretested 170 men and women aged 20 to 70 years over a 3-session baseline period, with posttests at 6 months. Outcomes included clinic and ambulatory blood pressure, quality of life, left ventricular mass measured by M-mode echocardiography, left ventricular diastolic function measured by Doppler, and carotid atherosclerosis measured by beta-mode ultrasound. This trial was designed to evaluate the hypothesis that a selected stress reduction technique is effective in reducing hypertension and hypertensive heart disease in African Americans.

A randomized controlled trial of stress reduction in African Americans treated for hypertension for over one year.

Abstract:
Psychosocial stress has been implicated in the disproportionately higher rates of hypertension among African Americans. This randomized controlled trial compared the effects of two stress reduction techniques and a health education control program on hypertension during a period of 1 year in African-American men and women (N = 150, mean age 49 +/- 10 years, mean blood pressure (BP) = 142/95 mm Hg) at an urban community health center.

Interventions included 20 min twice a day of Transcendental Meditation (TM) or progressive muscle relaxation (PMR), or participation in conventional health education (HE) classes. All subjects continued usual medical care. Outcomes assessed were systolic BP and diastolic BP at 3, 6, 9, and 12 months after treatment, analyzed by repeated measures ANCOVA.

The TM group showed decreases in systolic BP/diastolic BP of -3.1/-5.7 mm Hg compared to -0.5/-2.9 mm Hg for PMR or HE, (P = .12 to .17 for systolic BP, P = .01 for diastolic BP). In addition the TM group demonstrated reduced use of antihypertensive medication relative to increases for PMR (P = .001) and HE (P = .09) groups. Group analysis by gender showed that women practicing TM had decreased BP (-7.3/-6.9 mm Hg) significantly more than women practicing PMR (0.7/-2.7 mm Hg) or HE (-.07/-3.0 mm Hg) (P .01 to .03). The change in men praticing TM (0.2 /-4.7 mm Hg) was greater than men practicing HE (-0.9/-2.0 mm Hg) for diastolic BP only (P = .09,) and not different from PMR men (-2.0/-3.1).

A selected stress reduction approach, the Transcendental Meditation program, may be useful as an adjunct in the long-term treatment of hypertension in African Americans.

Effects of a randomized controlled trial of transcendental meditation on components of the metabolic syndrome in subjects with coronary heart disease.

Abstract:
The metabolic syndrome is thought to be a contributor to coronary heart disease (CHD), and components of the syndrome have been identified as possible therapeutic targets. Previous data implicate neurohumoral activation related to psychosocial stress as a contributor to the metabolic syndrome. The aim of this study was to evaluate the efficacy of transcendental meditation (TM) on components of the metabolic syndrome and CHD.

We conducted a randomized, placebo-controlled clinical trial of 16 weeks of TM or active control treatment (health education), matched for frequency and time, at an academic medical center in a total of 103 subjects with stable CHD. Main outcome measures included blood pressure, lipoprotein profile, and insulin resistance determined by homeostasis model assessment (calculated as follows: [(fasting plasma glucose level [in milligrams per deciliter] x fasting plasma insulin level [in microunits per milliliter]) x 0.0552]/22.5); endothelial function measured by brachial artery reactivity testing; and cardiac autonomic system activity measured by heart rate variability.

The TM group had beneficial changes (measured as mean +/- SD) in adjusted systolic blood pressure (-3.4 +/- 2.0 vs 2.8 +/- 2.1 mm Hg; P = .04), insulin resistance (-0.75 +/- 2.04 vs 0.52 +/- 2.84; P = .01), and heart rate variability (0.10 +/- 0.17 vs -0.50 +/- 0.17 high-frequency power; P = .07) compared with the health education group, respectively. There was no effect of brachial artery reactivity testing.

Use of TM for 16 weeks in CHD patients improved blood pressure and insulin resistance components of the metabolic syndrome as well as cardiac autonomic nervous system tone compared with a control group receiving health education. These results suggest that TM may modulate the physiological response to stress and improve CHD risk factors, which may be a novel therapeutic target for the treatment of CHD.

A randomized controlled trial on effects of the Transcendental Meditation program on blood pressure, psychological distress, and coping in young adults.

Abstract:
Psychological distress contributes to the development of hypertension in young adults. This trial assessed the effects of a mind-body intervention on blood pressure (BP), psychological distress, and coping in college students.

This was a randomized controlled trial (RCT) of 298 university students randomly allocated to either the Transcendental Meditation (TM) program or wait-list control. At baseline and after 3 months, BP, psychological distress, and coping ability were assessed. A subgroup of 159 subjects at risk for hypertension was analyzed similarly.

Changes in systolic BP (SBP)/diastolic BP (DBP) for the overall sample were -2.0/-1.2 mm Hg for the TM group compared to +0.4/+0.5 mm Hg for controls (P = 0.15, P = 0.15, respectively). Changes in SBP/DBP for the hypertension risk subgroup were -5.0/-2.8 mm Hg for the TM group compared to +1.3/+1.2 mm Hg for controls (P = 0.014, P = 0.028, respectively). Significant improvements were found in total psychological distress, anxiety, depression, anger/hostility, and coping (P values < 0.05). Changes in psychological distress and coping correlated with changes in SBP (P values < 0.05) and DBP (P values < 0.08).

This is the first RCT to demonstrate that a selected mind-body intervention, the TM program, decreased BP in association with decreased psychological distress, and increased coping in young adults at risk for hypertension. This mind-body program may reduce the risk for future development of hypertension in young adults.

Testing the effectiveness of a mindfulness-based intervention to reduce emotional distress in outpatients with diabetes (DiaMind): design of a randomized controlled trial.

Abstract:
Approximately 20-40% of outpatients with diabetes experience elevated levels of emotional distress, varying from disease-specific distress to general symptoms of anxiety and depression. The patient's emotional well-being is related to other unfavorable outcomes, like reduced quality of life, sub-optimal self-care, impaired glycemic control, higher risk of complications, and increased mortality rates. The purpose of this study is to test the effectiveness of a new diabetes-specific, mindfulness-based psychological intervention. First, with regard to reducing emotional distress; second, with respect to improving quality of life, dispositional mindfulness, and self-esteem of patients with diabetes; third, with regard to self-care and clinical outcomes; finally, a potential effect modification by clinical and personality characteristics will be explored.

The Diabetes and Mindfulness study (DiaMind) is a randomized controlled trial. Patients with diabetes with low levels of emotional well-being will be recruited from outpatient diabetes clinics. Eligible patients will be randomized to an intervention group or a wait-list control group. The intervention group will receive the mindfulness program immediately, while the control group will receive the program eight months later. The primary outcome is emotional distress (anxiety, stress, depressive symptoms), for which data will be collected at baseline, four weeks, post intervention, and after six months follow-up. In addition, self-report data will be collected on quality of life, dispositional mindfulness, self-esteem, self-care, and personality, while complications and glycemic control will be assessed from medical files and blood pressure will be measured. Group differences will be analyzed with repeated measures analysis of covariance.The study is supported by grants from the Dutch Diabetes Research Foundation and Tilburg University and has been approved by a medical ethics committee.

It is hypothesized that emotional well-being, quality of life, dispositional mindfulness, self-esteem, self-care, and blood pressure will improve significantly more in the mindfulness group compared to the control group. Results of this study can contribute to a better care for patients with diabetes with lowered levels of emotional well-being. It is expected that the first results will become available in 2012.

Dutch Trial Register NTR2145.

Buddhist group therapy for diabetes patients with depressive symptoms.

Abstract: The objective of this study was to assess the effect of Buddhist group therapy on patients with type 2 diabetes who had depressive symptoms. A quasi-experimental design study using a control group with matching technique was conducted. After informed consent was obtained, the "Nine questions for assessing depressive disorder symptom" (Isan language) was used to determine the patient's condition. A total of 62 patients with type 2 diabetes who had depressive symptoms were assigned to either the experimental group (n = 32) or the control group (n = 32). Patients in the experimental group were divided further into four groups (8 patients per group) and attended the Buddhist group therapy. The intervention consisted of a weekly Buddhist group gathering lasting 2 hours for 6 weeks plus home meditation practices. Patients in the control group received treatment as usual. Both groups received standard physician treatment, including medication. Physicians did not know who was in either the control or experimental groups. Results show that 6 months after the intervention, 65.6% and 100% of patients in the control group and experimental group, respectively, returned to normal level. The intention-to-treat analysis, which included two participants in the experimental group lost follow-up, yielded a small reduction in the number of patients who returned to normal level (93.8%). With intention-to-treat analysis, the relative risk on depressive symptoms between the experimental and control groups was 6.5 (95% confidence interval, 1.4-30.6). Qualitative data from the experimental group supported that there were therapeutic group factors involved. However, patients realized the truth of being oneself and also accepted their current living condition. In conclusion, this program is effective in reducing depressive symptoms.

Mindfulness training for smoking cessation: results from a randomized controlled trial.

Abstract:
Cigarette smoking is the leading cause of preventable death in the world, and long-term abstinence rates remain modest. Mindfulness training (MT) has begun to show benefits in a number of psychiatric disorders, including depression, anxiety and more recently, in addictions. However, MT has not been evaluated for smoking cessation through randomized clinical trials.

88 treatment-seeking, nicotine-dependent adults who were smoking an average of 20cigarettes/day were randomly assigned to receive MT or the American Lung Association's freedom from smoking (FFS) treatment. Both treatments were delivered twice weekly over 4 weeks (eight sessions total) in a group format. The primary outcomes were expired-air carbon monoxide-confirmed 7-day point prevalence abstinence and number of cigarettes/day at the end of the 4-week treatment and at a follow-up interview at week 17.

88% of individuals received MT and 84% of individuals received FFS completed treatment. Compared to those randomized to the FFS intervention, individuals who received MT showed a greater rate of reduction in cigarette use during treatment and maintained these gains during follow-up (F=11.11, p=.001). They also exhibited a trend toward greater point prevalence abstinence rate at the end of treatment (36% vs. 15%, p=.063), which was significant at the 17-week follow-up (31% vs. 6%, p=.012).

This initial trial of mindfulness training may confer benefits greater than those associated with current standard treatments for smoking cessation.

Mindfulness Intervention for Stress Eating to Reduce Cortisol and Abdominal Fat among Overweight and Obese Women: An Exploratory Randomized Controlled Study.

Abstract: Psychological distress and elevated cortisol secretion promote abdominal fat, a feature of the Metabolic Syndrome. Effects of stress reduction interventions on abdominal fat are unknown. Forty-seven overweight/obese women (mean BMI = 31.2) were randomly assigned to a 4-month intervention or waitlist group to explore effects of a mindfulness program for stress eating. We assessed mindfulness, psychological distress, eating behavior, weight, cortisol awakening response (CAR), and abdominal fat (by dual-energy X-ray absorptiometry) pre- and posttreatment. Treatment participants improved in mindfulness, anxiety, and external-based eating compared to control participants. Groups did not differ on average CAR, weight, or abdominal fat over time. However, obese treatment participants showed significant reductions in CAR and maintained body weight, while obese control participants had stable CAR and gained weight. Improvements in mindfulness, chronic stress, and CAR were associated with reductions in abdominal fat. This proof of concept study suggests that mindfulness training shows promise for improving eating patterns and the CAR, which may reduce abdominal fat over time.

Changes in stress, eating, and metabolic factors are related to changes in telomerase activity in a randomized mindfulness intervention pilot study.

Abstract:
Psychological distress and metabolic dysregulation are associated with markers of accelerated cellular aging, including reduced telomerase activity and shortened telomere length. We examined whether participation in a mindfulness-based intervention, and, secondarily, improvements in psychological distress, eating behavior, and metabolic factors are associated with increases in telomerase activity in peripheral blood mononuclear cells (PBMCs).

We enrolled 47 overweight/obese women in a randomized waitlist-controlled pilot trial (n=47) of a mindfulness-based intervention for stress eating and examined changes in telomerase activity from pre- to post-intervention. In secondary analyses, changes in telomerase activity across the sample were examined in relation to pre- to post-intervention changes in psychological distress, eating behavior, and metabolic factors (weight, serum cortisol, fasting glucose and insulin, and insulin resistance).

Both groups increased in mean telomerase activity over 4 months in intent-to-treat and treatment efficacy analyses (p<0.001). Nonsignificant trends showed that greater attendance was associated with increases in telomerase, and telomerase increases were 18% higher among 'as treated' participants compared to controls. Across groups, changes in chronic stress, anxiety, dietary restraint, dietary fat intake, cortisol, and glucose were negatively correlated with changes in telomerase activity. In exploratory analyses, decreases in dietary fat intake partially mediated the association between dietary restraint and telomerase activity with marginal significance.

While there was no clear effect of the intervention on telomerase activity, there was a striking pattern of correlations between improvements in psychological distress, eating behavior, and metabolic health and increases in telomerase activity. These findings suggest that telomerase activity may be in part regulated by levels of both psychological and metabolic stress.


Context: Stimulant use disorder is a continuously growing medical and social burden without approved medications available for its treatment. Psychosocial interventions could be a valid approach to help people reduce or cease stimulant consumption. This is an update of a Cochrane review first published in 2016.

To assess the efficacy and safety of psychosocial interventions for stimulant use disorder in adults.

We included randomised controlled trials (RCTs) comparing any psychosocial intervention with no intervention, treatment as usual (TAU), or a different intervention in adults with stimulant use disorder.

Continuing care for cocaine dependence: comprehensive 2-year outcomes.

Abstract: This report presents 2-year outcome data from an outpatient continuing care study in which cocaine-dependent patients (N = 132) were randomly assigned to either standard group counseling (STND) or individualized relapse prevention (RP). Data on cocaine outcomes during the 6-month treatment phase of the study were presented in an earlier report (J. R. McKay, A. I. Alterman, J. S. Cacciola, M. R. Rutherford, & C. P. O'Brien, 1997). In the present report, a continuing care condition main effect was obtained on only 1 of 8 outcome variables examined. However, patients who endorsed a goal of absolute abstinence on entering continuing care had better cocaine use outcomes in RP than in STND, whereas the opposite was the case for those with less stringent abstinence goals. In addition, patients with current cocaine or alcohol dependence on entering continuing care who received RP had better cocaine use outcomes in Months 1-6 and better alcohol use outcomes in Months 13-24 than those in STND.

The effectiveness of the Minnesota Model approach in the treatment of adolescent drug abusers.

Abstract:
The treatment outcome of drug-abusing adolescents treated with a 12-Step approach.

The study compares drug use outcome data at 6 and 12 months post-treatment among three groups of adolescents: those who completed treatment, those who did not and those on a waiting list. Also, among treatment completers, residential and outpatient samples were compared on outcome.

The treatment site is located in the Minneapolis/St Paul area of Minnesota.

Two hundred and forty-five drug clinic-referred adolescents (12-18 years old), all of whom met at least one DSM-III-R substance dependence disorder. One hundred and seventy-nine subjects received either complete or incomplete 12-Step, Minnesota Model treatment and 66 were waiting list subjects.

In addition to demographics and clinical background variables, measures included treatment involvement, treatment setting and drug use frequency at intake and follow-up.

Absolute and relative outcome analyses indicated that completing treatment was associated with far superior outcome compared to those who did not complete treatment or receive any at all. The percentage of treatment completers who reported either abstinence or a minor lapse for the 12 months following treatment was 53%, compared to 15 and 28% for the incompleter and waiting list groups, respectively.

Favorable treatment outcome for drug abuse was about two to three times more likely if treatment was completed. Also, there were no outcome differences between residential and outpatient groups. Alcohol was the most common drug used during the follow-up period, despite cannabis being the preferred drug at intake.

Brief coping skills treatment for cocaine abuse: 12-month substance use outcomes.

Abstract: Patients (N = 108) in a study of cocaine-specific coping skills training (CST), which was found to reduce cocaine use during a 3-month follow-up, were followed for an additional 9 months. CST involved coping skills training in the context of high-risk situations. Control treatment used meditation-relaxation. Both were added to comprehensive private substance abuse treatment. Patients in CST who relapsed had significantly fewer cocaine use days than did the control group during the first 6 months, then both conditions did equally well. Patients in CST also drank alcohol more frequently in the last 6 months than did contrast patients but did not differ in heavy drinking days. For cocaine use outcomes, no interaction of treatment was found with gender, education, route of administration, drug use severity, sociopathy, or depression. Implications include the need to investigate different lengths and combinations of treatment.

A reinforcement-based therapeutic workplace for the treatment of drug abuse: six-month abstinence outcomes.

Abstract: This study evaluated a novel drug abuse treatment, the Therapeutic Workplace. In this treatment, patients are paid to perform jobs or to participate in job training. Salary is linked to abstinence by requiring patients to provide drug-free urine samples to gain access to the workplace. Pregnant and postpartum drug abuse patients (N = 40) were randomly assigned to a Therapeutic Workplace or usual care control group. Therapeutic Workplace participants were invited to work 3 hr every weekday for 6 months and could earn up to $4,030 in vouchers for abstinence, workplace attendance, and performance. On average, 45% of participants attended the workplace per day. Relative to controls, the Therapeutic Workplace nearly doubled patients' abstinence from opiates and cocaine (33% vs. 59% of thrice-weekly urine samples drug negative, respectively, p < .05). The Therapeutic Workplace can effectively treat heroin and cocaine abuse in pregnant and postpartum women.

A dose response study of cognitive behavioral therapy in cocaine abusers.

Abstract: In order to evaluate the effect of frequency of counseling sessions, we studied retention, cocaine use and craving, and psychiatric symptoms of 68 cocaine-dependent outpatients randomly assigned to twice weekly, once weekly, or biweekly sessions in a 12-week treatment program that utilized manual-based, individual cognitive behavioral psychotherapy. All participants were tested and monitored twice a week. Retention was comparable among treatment groups, and improvement was found regardless of counseling frequency. Cocaine use (urine toxicology and self-report), cocaine craving (VAS), and total psychiatric symptoms (SCL-90) decreased by modest but statistically significant (p < 0.05) amounts in all treatment groups. Findings suggest that cognitive behavioral therapy is effective in reducing cocaine use even if a less intensive schedule is used.

The effectiveness of telephone-based continuing care in the clinical management of alcohol and cocaine use disorders: 12-month outcomes.

Abstract: This study of continuing care for substance dependent patients compared a telephone-based monitoring and brief counseling intervention (TEL) with 2 face-to-face interventions, relapse prevention (RP) and standard 12-step group counseling (STND). The participants were graduates of intensive outpatient programs who had current dependence on alcohol and/or cocaine. Self-report, collateral, and biological measures of alcohol and cocaine use were obtained over a 12-month follow-up. The treatment groups did not differ on abstinence-related outcomes in the complete sample (N = 359) or on cocaine use outcomes in participants with cocaine dependence (n = 268). However, in participants with alcohol dependence only (n = 91), TEL produced better alcohol use outcomes than STND on all measures examined and better outcomes than RP on some of the measures.

The effectiveness of telephone-based continuing care for alcohol and cocaine dependence: 24-month outcomes.

Abstract:
Telephone-based disease management protocols have shown promise in improving outcomes in a number of medical and psychiatric disorders, but this approach to continuing care has received little study in alcohol- and drug-dependent individuals.

To compare telephone-based continuing care with 2 more intensive face-to-face continuing care interventions.

A randomized 3-group clinical trial with a 2-year follow-up.

Two outpatient substance abuse treatment programs, one community-based and the other at a Veterans Affairs medical center facility.

Alcohol- and/or cocaine-dependent patients (N = 359) who had completed 4-week intensive outpatient programs.

Three 12-week continuing care treatments: weekly telephone-based monitoring and brief counseling contacts combined with weekly supportive group sessions in the first 4 weeks (TEL), twice-weekly cognitive-behavioral relapse prevention (RP), and twice-weekly standard group counseling (STND).

Percentage of days abstinent from alcohol and cocaine, total abstinence from alcohol and cocaine, negative consequences of substance use, cocaine urine toxicological results, and gamma-glutamyltransferase.

Participants in TEL had higher rates of total abstinence over the follow-up than those in STND (P<.05). In alcohol-dependent participants, 24-month gamma-glutamyltransferase levels were lower in TEL than in RP (P = .005). In cocaine-dependent participants, there was a significant group x time interaction (P = .03) in which the rate of cocaine-positive urine samples increased more rapidly in RP as compared with TEL. On percentage of days abstinent or negative consequences of substance use, TEL did not differ from RP or STND. Participants with high scores on a composite risk indicator, based on co-occurring alcohol and cocaine dependence and poor progress toward achieving intensive outpatient program goals, had better total abstinence outcomes up to 21 months if they received STND rather than TEL, whereas those with lower scores had higher abstinence rates in TEL than in STND (P = .04).

Telephone-based continuing care appears to be an effective form of step-down treatment for most patients with alcohol and cocaine dependence who complete an initial stabilization treatment, compared with more intensive face-to-face interventions. However, high-risk patients may have better outcomes if they first receive group counseling continuing care after completing intensive outpatient programs.

Reinforcement-based therapy: 12-month evaluation of an outpatient drug-free treatment for heroin abusers.

Abstract: This controlled study examined the efficacy of reinforcement-based therapy (RBT) for producing enhanced abstinence outcomes over 12 months in opioid-dependent patients exiting a brief residential detoxification. Patients were randomly assigned upon completing their medically managed taper (i.e., detoxification) to RBT (N=66) or usual care (N=64) referral to community treatment programs. The 6-month RBT program offered an array of abstinence-based incentives including rent payment for recovery housing, program-led recreational activities and skills training for procuring employment. RBT produced significantly higher self-report and urinalysis-confirmed rates of abstinence from opioids and cocaine relative to usual care at 1 (42% versus 15%) and 3 (38% versus 17%) months during treatment but not at 6 or 12 months after enrollment. The RBT but not the usual care group showed significant increases in the number of days worked and the amount of legal income earned at 3, 6 and 12 months. The results of this randomized study suggest that an intensive reinforcement-based therapy that includes abstinence-based recovery housing is a promising approach; however, further research is needed to determine the role of treatment intensity and the specific efficacy of RBT's component parts.

Motivationally enhanced group counseling for substance users in a soup kitchen: a randomized clinical trial.

Abstract: Soup kitchens tend to serve residentially unstable adults characterized by a high prevalence of substance abuse. In this study, 289 soup kitchen guests who reported drug or alcohol problems were randomly assigned to information and referral (I&R) plus peer advocacy (peers encouraging subjects to participate in other services) (N = 139) or to an experimental 12-session motivational group (three sessions per week for 4 weeks) followed by a 36-session cognitive-behavioral group (three sessions per week for 12 weeks), plus I&R and peer advocacy. Mean age was 42; 82% male; 68% African-American; 81% unstable residence; 14% HIV+. Experimentals were significantly more likely than the controls to have increased their participation in some type of substance abuse intervention during the follow-up period. In addition, experimentals were significantly more likely than controls to have reduced both drinking and heavy drinking at follow-up (there was no difference between groups in reduction of cocaine use). Interaction analysis indicated that the experimental intervention was more effective for participants with higher rather than lower substance abuse severity at baseline. These results support the concept that motivationally enhanced group counseling, provided as a low-threshold outreach intervention, can help to increase participation in formal treatment and 12-step groups and to reduce substance abuse, particularly for those starting with high severity of use.

A randomized clinical trial of a new behavioral treatment for drug abuse in people with severe and persistent mental illness.

Abstract:
Drug abuse by people with severe mental disorder is a significant public health problem for which there is no empirically validated treatment.

To evaluate the efficacy of a new behavioral treatment for drug abuse in this population: Behavioral Treatment for Substance Abuse in Severe and Persistent Mental Illness (BTSAS).

Participants were randomly assigned to 6 months of treatment in either BTSAS or a manualized control condition: Supportive Treatment for Addiction Recovery (STAR).

Treatment was conducted in community-based outpatient clinics and a Veterans Affairs medical center in Baltimore, Md.

Participants were 129 stabilized outpatients meeting DSM criteria for drug dependence (cocaine, heroin, or cannabis) and serious mental illness: 39.5% met DSM-IV criteria for schizophrenia or schizoaffective disorder; 55.8%, for major affective disorders; and the remainder met criteria for severe and persistent mental illness and other Axis I disorders.

Both treatments were administered by trained health care professionals in small groups, twice a week for 6 months. The BTSAS program is a social learning intervention that includes motivational interviewing, a urinalysis contingency, and social skills training. The control condition, STAR, is a supportive group discussion treatment. Main Outcome Measure The primary outcome measure was urinalysis results from twice-weekly treatment sessions.

The BTSAS program was significantly more effective than STAR in percentage of clean urine test results, survival in treatment, and attendance at sessions. The BTSAS program also had significant effects on important community-functioning variables, including hospitalization; money available for living expenses; and quality of life.

The BTSAS program is an efficacious treatment. Further work needs to be done to increase the proportion of eligible patients who are able to become engaged in treatment.