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References | PMC10120228 | |||
Purpose | IIH, HVF | IDIOPATHIC INTRACRANIAL HYPERTENSION | This study was designed to determine if point analysis of the Humphrey visual field (HVF) is an effective outcome measure for people with idiopathic intracranial hypertension (IIH) compared with mean deviation (MD). | PMC10153590 |
Methods | IIH | Using the IIH Weight Trial data, we performed a pointwise analysis of the numerical retinal sensitivity. We then defined a medically treated cohort as having MDs between −2 dB and −7 dB and calculated the number of points that would have the ability to change by 7 dB. | PMC10153590 | |
Results | BLIND | The HVF 24-2 mean ± SD MD in the worse eye was −3.5 ± 1.1 dB (range, −2.0 to −6.4 dB). Total deviation demonstrated a preference for the peripheral and blind spot locations to be affected. Points between 0 dB and −10 dB demonstrated negligible ability to improve, compared with those between −10 dB and −25 dB. For the evaluation of the feasibility for a potential medical intervention trial, only 346 points were available for analysis between −10 dB and −25 dB bilaterally, compared with 4123 points in baseline sensitivities of 0 to −10 dB. | PMC10153590 | |
Conclusions | IIH | Patients with IIH have mildly affected baseline sensitivities in the visual field based on HVF analyzer findings, and the majority of points do not show substantial change over 24 months in the setting of a randomized clinical trial. Most patients with IIH who are eligible for a medical treatment trial generally have the mildest affected baseline sensitivities. In such patients, pointwise analysis offers no advantage over MD in detection of visual field change. | PMC10153590 | |
Introduction | visual loss, IIH, visual field damage, visual field defects, papilledema, optic neuropathy | IDIOPATHIC INTRACRANIAL HYPERTENSION, OPTIC NEUROPATHY, PAPILLEDEMA | Idiopathic intracranial hypertension (IIH) is characterized by raised intracranial pressure (ICP) associated, in most cases, with papilledema, visual field defects, and, in some cases, permanent visual loss.The Humphrey visual field (HVF) mean deviation (MD) has been used as an endpoint in IIH clinical trials.There are a number of different ways to evaluate visual field damage.Another functional endpoint that has been recommended for an optic neuropathy treatment trial is a change of 7 dB in five or more predefined reproducible visual locations. | PMC10153590 |
Materials and Methods | IIH | WEST | IIH:WT was a prospective, multi-center, open-label, parallel-group, controlled trial in which participants with IIH were randomized in a 1:1 ratio to a bariatric surgery pathway or the Weight Watchers program, a community weight management intervention (CWI). The study was approved by the Ethics Review Board of the National Research Ethics Committee West Midlands, and the Black Country approved IIH:WT (14/WM/0011). In accordance with the Declaration of Helsinki, all subjects gave written informed consent to participate in the study, and the detailed clinical trial methodology has been published. | PMC10153590 |
Subjects | IIH | Women (18–55 years old) with a body mass index (BMI) > 35 kg/m2 were eligible if they had a clinical diagnosis of active IIH according to criteria outlined by Friedman et al. | PMC10153590 | |
Acquisition of Data From the Visual Fields | HVFs | In this analysis, the raw values of the patient's retinal sensitivity at each of the HVF 24-2 predetermined points were extracted from pdf scans of the HVFs using a custom data extraction tool based on the Python | PMC10153590 | |
HVF Analysis | To detect pointwise change over the course of the study, the points were categorized by individual pointwise retinal sensitivity at baseline. The mean change in sensitivity was plotted at each point from baseline to 12 and 24 months. Subsequently, the cohort was restricted to a population defined by a baseline MD between −2 dB and −7 dB to simulate a medically managed population. Finally, the number of points in the visual field in the whole cohort and in the restricted simulated medically treated cohort that would be expected to change per sensitivity category were calculated. | PMC10153590 | ||
Statistical Analysis | Analysis of clinical data was based on the full dataset according to the statistical analysis plan. | PMC10153590 | ||
Results | IIH | Characteristics of the study population are summarized in IIH:WT Baseline CharacteristicsIQR, interquartile range; CSF, cerebrospinal fluid; BMI, body mass index.Missing data are indicated in parentheses.
| PMC10153590 | |
Pointwise Location Sensitivity for Whole Cohort at 12 and 24 Months | ± | SENSITIVITY | Points with baseline sensitivities between 0 dB and −10 dB showed small changes over time points (0–5 dB, mean 0.02 ± 3.1; −5 to −10 dB, mean 2.4 ± 4.7 at 12 months) (
Number of Points and Mean Change in Point Sensitivity in Visual Field Test Locations Categorized by the Baseline Point Sensitivity Subgroup at 12 and 24 MonthsNumber of Points and Mean Change in Point Sensitivity Over Time in Test Locations With a Baseline Point Sensitivity Between −10 dB and −25 dB, Categorized by Trial Arm and Use of Acetazolamide | PMC10153590 |
Analysis of Pointwise Sensitivities in the Simulated Medically Managed Cohort | SENSITIVITY | Those with a MD between −2 dB and −7 dB at baseline had a similar distribution of changes in the point-sensitive deviation at baseline (Subanalysis (Defined by MD Between −2 dB and −7 dB at Baseline) to Simulate a Medically Treated Cohort Where the Number of Point Sensitivities Are Categorized by the Location Point Sensitivity | PMC10153590 | |
Analysis of Pointwise Sensitivities in the Whole Cohort | IIH | SENSITIVITY | The utility of baseline points between −0 dB and −10 dB was examined to establish how point-sensitivity analysis performed in IIH:WT. As expected, these demonstrated very little change at 12 and 24 months (at 12 months, the mean change was 0.4 ± 3.5 dB; at 24 months, the mean change was 0.48 ± 4.11 dB). Baseline sensitivities between −10 dB and −25 dB have the ability to change over time (Longitudinal Mean Pointwise Location Sensitivity Changes in Those With Point Sensitivities Between −10 dB and −25 dB, Categorized by Treatment at 12 and 24 Months | PMC10153590 |
Categorizing the Population by Baseline MD | IIH | EYE, SENSITIVITY | To understand how representative a baseline point sensitivity beyond −10 dB in one or more points was in an active IIH population, we calculated the number of points ≥ −10 dB in each individual (Number of Participants Who Had One or More Baseline Points in Either Eye With a Sensitivity Worse Than −10 dB in the Entire Cohort With and Without Perimetric MD CriteriaThe median number of points ≤ −10 dB in either eye at baseline (and IQR) in only those patients who had at least one qualifying point.Percentage and Number of Participants Who Had Pointwise Improvement of 7 dB or More From Baseline at 12 and 24 Months | PMC10153590 |
Discussion | visual field loss, IIH, glaucoma | GLAUCOMA | In this study, we characterized the pointwise pattern of visual field change in a cohort of people with active IIH recruited to the IIH:WT. Those with baseline point sensitivities between 0 dB and −10 dB showed small changes over time and, as expected, were unlikely to demonstrate clinically meaningful change over both 12 and 24 months. Points in the −10 to −25 dB category demonstrated change that could be considered clinically meaningful (mean of 8.5 dB in at least one point in the whole visual field); however, using data between −10 dB and −25 dB resulted in fewer data points and larger SDs for analysis. Although the median number of points worse than −10 dB was five, 43% of all of the IIH:WT participants had fewer than two points worse than −10 dB at baseline, emphasizing that data points worse than −10 dB were not representative of the majority of IIH patients.It should be emphasized that eligibility for the IIH:WT was not determined by MD criteria. Therefore, to simulate the HVF data to reflect a typically medically managed cohort, we chose a baseline HVF in which the MD was between −2 dB and −7 dB (the criterion range used in the IIHTTThere is no universally adopted, minimally clinically important change in HVF measures in IIH as there are in glaucoma.A limitation of this study is that it included only patients with well-established IIH. Thus, the results may not be applicable to patients with recently diagnosed IIH or to severely affected patients who may require urgent surgery.In this study and in studies reported by others,Our data indicate that point analysis of the HVF has no advantage over global MD analysis, at least in the population we studied from the IIH:WT. As expected, baseline points that were better than −10 dB had little room to improve over time and, thus, offered little utility for analysis. If the generic threshold for a clinically meaningful change of 7 dB is recommended for IIH treatment trials, baseline points in the range of −10 to −25 dB would be needed for analysis. The US Food and Drug Administration has stated that visual field loss has likely occurred if ≥5 visual field locations have significant change beyond the 5% probability level or if there is at least a 7-dB between-group mean difference for the entire field. | PMC10153590 |
Acknowledgments | THORN | Supported by a National Institute for Health Research clinician scientist fellowship (NIHR-CS-011-028 to AJS); by the Medical Research Council, UK (MR/K015184/1 to AJS); and by a Sir Jules Thorn Award for Biomedical Science (to AJS). The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health and Social Care.Disclosure: | PMC10153590 | |
References | PMC10153590 | |||
Subject terms | SURMOUNT-3, overweight or obesity, weight loss, weight reduction | The effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on weight reduction after successful intensive lifestyle intervention are unknown. This double-blind, placebo-controlled trial randomized (1:1) adults with body mass index ≥30 or ≥27 kg/mIn the SURMOUNT-3 trial, once-weekly treatment with tirzepatide was demonstrated to result in clinically meaningful additional weight loss in adults with overweight or obesity following initial successful weight loss of at least 5% body weight with intensive lifestyle intervention. | PMC10667099 | |
Main | obesity, weight reduction | OBESITY, ADVERSE EFFECTS, COMPLICATIONS | The adverse effects of obesity are well known to healthcare professionals and persons who live with this chronic diseaseIntensive lifestyle intervention is recommended as the cornerstone of obesity managementNew incretin-based, antiobesity medications could bolster the results of intensive lifestyle interventionExpert panels have suggested the use of antiobesity medications following intensive lifestyle intervention to induce additional weight reduction (which may be needed to achieve optimal control of obesity-related complications) or, at a minimum, to prevent weight regain | PMC10667099 |
Results | PMC10667099 | |||
Patient disposition | PMC10667099 | |||
Intensive lifestyle intervention lead-in period | A total of 972 participants were assessed for eligibility at screening, of whom 806 were enrolled into the 12-week intensive lifestyle intervention lead-in period (Fig. | PMC10667099 | ||
Primary outcomes | Figure | PMC10667099 | ||
Secondary outcomes | PMC10667099 | |||
Change in body weight | At week 72, more participants on tirzepatide MTD than placebo achieved reductions in body weight of ≥10, ≥15 and ≥20% from randomization (At 72 weeks, for the TRE, 94.0% (270) of participants in the tirzepatide MTD group maintained ≥80% of body weight lost during the 12-week lead-in period compared with 43.8% (128) in the placebo group (OR 19.7; 95% CI 10.3, 37.6; Overall, for the TRE, intensive lifestyle intervention followed by 72 weeks of tirzepatide led to a total weight change of −24.3% compared with −4.5% with intensive lifestyle intervention followed by placebo (estimated treatment difference −19.9 percentage points (95% CI −23.5, −16.2) (Fig. Accordingly, there was a reduction in BMI with tirzepatide compared with placebo from randomization to week 72 (efficacy estimand: tirzepatide, −7.7 kg/m | PMC10667099 | ||
Cardiometabolic risk factors and physical function | At week 72 the change from randomization in waist circumference with tirzepatide MTD was superior to placebo using the TRE (tirzepatide, −14.6 cm versus placebo, 0.2 cm; estimated treatment difference, −14.8 cm (95% CI −17.2, −12.5; Participant-reported physical function improved more with tirzepatide than with placebo from randomization to week 72 (Table Changes in cardiometabolic parameters and patient-reported outcomes from the start of the lead-in period (week −12) to week 72 are reported in Extended Data Table | PMC10667099 | ||
Safety | pancreatitis | ADVERSE EVENTS, ADVERSE EVENT, PANCREATITIS | Overall, 87.1% of the 287 tirzepatide-treated participants reported at least one treatment-emergent adverse event compared with 76.7% of the 292 placebo-treated participants (Table Serious adverse events were reported by 31 participants (5.4%) overall. Occurrence was similar in participants treated with tirzepatide (5.9%) and placebo (4.8%) (Table Adjudication-confirmed cases of pancreatitis were reported in 0.3% (one) of participants in the tirzepatide MTD group and 0.3% (one) of participants in the placebo group from randomization to safety follow-up (Table | PMC10667099 |
Exploratory outcomes | For the prespecified exploratory endpoint of achieving ≥25% body weight reduction from randomization, for the TRE, 28.7% (82) of tirzepatide-treated participants compared with 1.2% (four) in the placebo group met this target (OR 33.7 (95% CI 8.8, 128.5); Table | PMC10667099 | ||
Discussion | SURMOUNT-3, weight loss, overweight or obesity | Tirzepatide substantially increased the magnitude of weight loss when administered following an initial 12-week intensive lifestyle intervention that reduced baseline body weight by an average of 6.9% in successful program completers. As measured from randomization (week 0) to week 72, participants who received tirzepatide MTD of 10 or 15 mg lost an additional 18.4% of body weight, compared with a gain of 2.5% for placebo. In total, 87.5% of tirzepatide-treated participants lost an additional 5% or more of their randomization weight compared with 16.5% of placebo-treated participants, with tirzepatide also demonstrating superiority in the achievement of all other categorical weight losses. These findings indicate that individuals with overweight or obesity who have lost approximately 5–10% of their body weight with supervised lifestyle intervention—or potentially through their own self-directed diet and exercise efforts—could expect to achieve further clinically meaningful weight loss with the addition of tirzepatide.The strength of tirzepatide is underscored by comparison with a similarly designed trial of liraglutide (3.0 mg), approved for chronic weight management. After losing an average 6.0% of baseline weight in a comparable lead-in program, participants who received liraglutide achieved an additional 6.2% reduction in randomization weight at 56 weeks compared with a 0.2% reduction for placeboThe cumulative 24.3% reduction in body weight achieved with intensive lifestyle intervention, followed by tirzepatide, approximates the 1 year weight loss induced with sleeve gastrectomyThe safety profile of tirzepatide in this trial was consistent with findings from previous trials of tirzepatide when evaluated for the treatment of obesityMuch remains to be learned about how lifestyle intervention and the new incretin-based antiobesity medications can be optimally used together. If the goal of combining these therapies is to increase total weight loss, results of the present trial and SCALE-MAINTENANCEThe suggestion of additivity with sequential therapy, however, may be challenged by findings from preclinical studies. These studies have demonstrated that caloric restriction alone does not address the underlying physiology regulating body weight or fat mass, and antiobesity medication has the same overall ultimate effect regardless of whether or not caloric restriction preceded the medicationAnother major treatment issue concerns the intensity (that is, frequency) and scope of lifestyle intervention required with antiobesity medications. Weekly lifestyle visits and daily monitoring of food and energy intake historically have been required to help patients achieve and maintain the 500–750 kcal per day deficit needed to induce clinically meaningful weight lossThe strengths of this study, which included an intensive lifestyle lead-in, include the fact that it had a relatively large sample size in which over one-third of the randomized population were men and over half were of Hispanic ethnicity. In addition, a 72-week treatment period facilitated at least 52 weeks of treatment with tirzepatide at MTD. The allowance of dose de- and re-escalation during the titration phase helped to maximize tolerability and reflected dose adjustment strategies that may be relevant for clinical practice.The study’s limitations include that it was geographically restricted to North and South America and that the study population was predominantly white, thus potentially limiting the generalizability of the findings. In addition, the 17.5% of participants who did not lose at least 5% of baseline weight in the intensive lifestyle intervention were not randomized to medication. To the extent that response to lifestyle intervention may predict response to medication, exclusion of these participants may have resulted in a higher mean weight loss with tirzepatide MTD than would have been observed if lifestyle nonresponders had been included. Trials of the response to antiobesity medications in persons who are unsuccessful with intensive lifestyle intervention are needed, because lack of success with lifestyle interventions has been a common prerequisite for initiation of pharmacotherapy or bariatric surgery. Future studies evaluating both genetic and behavioral predictors of response to lifestyle intervention and pharmacotherapy will help inform clinical management even earlier in the course of treatment.In conclusion, in the SURMOUNT-3 trial, tirzepatide demonstrated clinically meaningful additional body weight reductions in adults with overweight or obesity following initial weight loss with intensive lifestyle intervention. | PMC10667099 | |
Methods | PMC10667099 | |||
Study design and participants | obesity, weight reduction | OBESITY | This 84-week, multicenter, randomized, parallel-arm, double-blind, placebo-controlled trial was conducted at 62 medical research centers in the USA, Argentina and Brazil. The study consisted of four periods: a 2-week screening period; a 12-week lead-in period during which participants received intensive lifestyle intervention to achieve ≥5.0% body weight reduction; a 72-week double-blind, placebo-controlled treatment period (including a 20-week dose escalation period); and a 4-week safety follow-up period (Extended Data Fig. Eligible participants were ≥18 years of age and had obesity (BMI ≥ 30 kg/m | PMC10667099 |
Inclusion criteria | Participants were eligible for inclusion in the study only if all of the following criteria applied: | PMC10667099 | ||
Type of participant and disease characteristics | ischemic cardiovascular disease, apneacardiovascular disease | HEART |
had a BMI of:≥30 kg/m≥27 kg/mhypertension: treated or with systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHgdyslipidemia: treated or with LDL ≥ 160 mg dlobstructive sleep apneacardiovascular disease (for example, ischemic cardiovascular disease, New York Heart Association Functional Classification Class I–III heart failure)had a history of at least one self-reported unsuccessful dietary effort to lose body weightin the investigator’s opinion, were well motivated, capable and willing to:learn how to self-inject study drug, as required for this protocol (visually impaired persons who were not able to perform the injections must have had the assistance of a sighted individual trained to inject the study drug; persons with physical limitations who were not able to perform the injections must have had the assistance of an individual trained to inject the study drug)inject study drug (or receive an injection from a trained individual if visually impaired or with physical limitations)follow study procedures for the duration of the study, including—but not limited to—following lifestyle advice (for example, dietary restrictions, exercise plan), maintaining a study diary and completing required questionnaires | PMC10667099 |
Participant characteristics | Mullerian agenesis, congenital anomaly | UTERUS |
were at least 18 years of age and age of majority according to local laws and regulationsmale participants:Male participants with partners of childbearing potential should have been willing to use reliable contraceptive methods throughout the study and for five half-lives of study drug plus 90 days, corresponding to 4 months after the last injection.female participants:Female participants not of childbearing potential may have participated and included those who were:infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy or tubal ligation) or congenital anomaly (such as Mullerian agenesis) orpostmenopausal—defined as either:a woman at least 40 years of age with an intact uterus, not on hormone therapy and who had cessation of menses for at least 1 year without an alternative medical cause, and follicle-stimulating hormone ≥40 mIU mlora woman 55 years or older not on hormone therapy and who had at least 12 months of spontaneous amenorrheaora woman at least 55 years of age with a diagnosis of menopause before starting hormone replacement therapyFemale participants of childbearing potential (not surgically sterilized and between menarche and 1 year postmenopausal) must have:tested negative for pregnancy at visit 1 based on a serum pregnancy testif sexually active, agreed to use two forms of effective contraception where at least one form was highly effective for the duration of the trial plus 30 days, corresponding to 2 months after the last injection; andnot have been breastfeedingNote: contraceptive use by men or women should have been consistent with local regulations regarding the methods of contraception for those participating in clinical studies. | PMC10667099 |
Informed consent |
Participants were required to be capable of giving signed informed consent, which included compliance with the requirements and restrictions listed in the informed consent form and in this protocol. | PMC10667099 | ||
Exclusion criteria | Participants were excluded from study enrollment if they met any of the following criteria at screening: | PMC10667099 | ||
Medical conditions | PMC10667099 | |||
Previous and/or concomitant therapy | obesity, ketoacidosis, monogenetic or syndromic forms, anxiety, malignancy, diabetes mellitus, psychiatric, myocardial infarctioncerebrovascular, autoimmune abnormality, ideation, anxiety disorder, bipolar disorder, weight gain, lupus, initiation of thyroid hormone replacement, schizophrenia, hypothyroidism, diabetes, gastric outlet obstruction) or chronically, suicide-related behaviors, medullary thyroid carcinoma, gastroparesis, polycystic ovarian syndrome, MDD, ideation or behavior, hypersensitivity, endocrinologic disorders, NAFLD, liver disease, alcohol abuse, eating disorder | OBESITY, RHEUMATOID ARTHRITIS, KETOACIDOSIS, SICKLE CELL DISEASE, SQUAMOUS CELL SKIN CANCER, NONALCOHOLIC FATTY LIVER DISEASE, DIABETES MELLITUS, HEART, IN SITU CARCINOMA, REMISSION, LUPUS, MULTIPLE ENDOCRINE NEOPLASIA SYNDROME TYPE 1, HYPOTHYROIDISM, SUBCLINICAL HYPOTHYROIDISM, DIABETES, MEDULLARY THYROID CARCINOMA, GASTROPARESIS, POLYCYSTIC OVARIAN SYNDROME, CHRONIC HEPATITIS, TYPE 2 DIABETES MELLITUS, GILBERT, PROSTATE CANCER, HYPERSENSITIVITY, DISORDER, UNCONTROLLED HYPERTENSION, DISEASE, LIVER DISEASE, CUSHING SYNDROME, HEMOLYTIC ANEMIAS |
had type 1 or type 2 diabetes mellitus, history of ketoacidosis or hyperosmolar state/comahad at least one laboratory value suggestive of diabetes mellitus during screening, including one or more of: HbA1c ≥6.5% (≥48 mmol mol
had a self-reported change in body weight >5 kg within 3 months before screeninghad a previous planned surgical treatment for obesity (excluding liposuction or abdominoplasty, if performed >1 year before screening)had or planned to have endoscopic and/or device-based therapy for obesity or had device removal within the past 6 months before screening:mucosal ablationgastric artery embolizationintragastric balloonduodenal–jejunal endoluminal liner
had renal impairment measured as eGFR < 30 ml minhad a known clinically important gastric emptying abnormality (for example, severe gastroparesis or gastric outlet obstruction) or chronically took drugs that directly affect GI motilityhad a history of chronic or acute pancreatitishad thyroid-stimulating hormone (TSH) outside of the range 0.4–6.0 mIU lNote: participants receiving treatment for hypothyroidism may have been included, provided their thyroid hormone replacement dose had been stable for at least 3 months and their TSH at screening fell within the range indicated above.Note: participants with a history of subclinical hypothyroidism but a TSH at screening within the range indicated above may have been included if, in the investigator’s opinion, the patient was unlikely to require initiation of thyroid hormone replacement during the course of the study.had obesity induced by other endocrinologic disorders (for example, Cushing syndrome) or diagnosed monogenetic or syndromic forms of obesity (for example, melanocortin 4 receptor deficiency or Prader–Willi syndrome)had a history of substantial active or unstable major depressive disorder (MDD) or other severe psychiatric disorder (for example, schizophrenia, bipolar disorder or other serious mood or anxiety disorder) within the past 2 yearsNote: participants with MDD or generalized anxiety disorder and whose disease state was considered stable for the past 2 years and was expected to remain stable throughout the course of the study, in the opinion of the investigator, may have been considered for inclusion if they were not on excluded medicationshad a lifetime history of suicide attempthad a PHQ-9 score of 15 or more at visit 1on the Columbia Suicide Severity Rating Scale (C-SSRS) at any time from visit 1 to visit 2:a ‘yes’ answer to Question 4 (active suicidal ideation with some intent to act, without specific plan) on the ‘Suicidal Ideation’ portion of the C-SSRSora ‘yes’ answer to Question 5 (active suicidal ideation with specific plan and intent) on the ‘Suicidal Ideation’ portion of the C-SSRSora ‘yes’ answer to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the ‘Suicidal Behavior’ portion of the C-SSRSandthe ideation or behavior occurred within the past monthhad uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg)had any of the following cardiovascular conditions within 3 months before visit 2:acute myocardial infarctioncerebrovascular accident (stroke)unstable anginahospitalization due to congestive heart failurehad New York Heart Association Functional Classification Class IV congestive heart failurehad acute or chronic hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (NAFLD) or any of the following, as determined by the central laboratory during screening:alanine aminotransferase level >3.0 times upper limit of normal (ULN) for the reference rangealkaline phosphatase level >1.5 times ULN for the reference rangetotal bilirubin level >1.2 times ULN for the reference range (except for cases of known Gilbert syndrome)Note: participants with NAFLD were eligible to participate in this trial if their alanine aminotransferase level was ≤3.0 times ULN for the reference range.had a serum calcitonin level (at visit 1) of≥20 ng l≥35 ng lhad a family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2had a history of an active or untreated malignancy or were in remission from a clinically important malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix or in situ prostate cancer) for <5 yearshad any other condition not listed in this section (for example, hypersensitivity or intolerance) that is a contraindication to GLP-1 R agonistshad a history of any other condition (such as known drug or alcohol abuse, diagnosed eating disorder or other psychiatric disorder) that, in the opinion of the investigator, may have precluded the participant from following and completing the protocolhad a history of use of marijuana or tetrahydrocannabinol-containing products within 3 months of enrollment, or unwillingness to abstain from marijuana or tetrahydrocannabinol-containing products use during the trialNote: if a participant had used cannabidiol oil during the past 3 months but agreed to refrain from use for the duration of the study, the participant could be enrolled.had had a transplanted organ (corneal transplants (keratoplasty) were allowed) or were awaiting an organ transplanthad any hematological condition that may have interfered with HbA1c measurement (for example, hemolytic anemias, sickle cell disease)
were receiving or had received within 3 months before screening chronic (>2 weeks or 14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, intra-articular or inhaled preparations) or had evidence of a substantial, active autoimmune abnormality (for example, lupus or rheumatoid arthritis) that had required (within the past 3 months) or was likely to require, in the opinion of the investigator, concurrent treatment with systemic glucocorticoids (excluding topical, intraocular, intranasal, intra-articular or inhaled preparations) during the course of the studyhad current treatment with or history of (within 3 months before visit 2) treatment with medications that may cause substantial weight gain, including but not limited to: tricyclic antidepressants, atypical antipsychotics and mood stabilizersExamples:imipramineamitriptylinemirtazapineparoxetinephenelzinechlorpromazinethioridazineclozapineolanzapinevalproic acid (and its derivatives) orlithiumNote: selective serotonin reuptake inhibitors other than paroxetine were permitted.had taken, within 3 months before visit 2, medications (prescribed or over-the-counter) or alternative remedies that promote weight lossExamples included, but were not limited toSaxenda (liraglutide 3.0 mg)Xenical/Alli (orlistat)Meridia (sibutramine)Acutrim (phenylpropanolamine)Sanorex (mazindol)Apidex (phentermine)BELVIQ (lorcaserin)Bontril (phendimetrazine)Qsymia (phentermine/topiramate combination)Contrave (naltrexone/bupropion)Note: use of metformin, or any other glucose-lowering medication, whether prescribed for polycystic ovarian syndrome or diabetes prevention, was not permitted.had started implantable or injectable contraceptives (such as Depo Provera) within 18 months before screening | PMC10667099 |
Previous and/or concurrent clinical study experience |
were currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this studywithin the past 30 days had participated in a clinical study and received treatment, whether active or placebo. If the study involved an investigational product, five half-lives or 30 days, whichever was longer, should have passed.had previously completed or withdrawn from this study or any other study investigating tirzepatide after receiving at least one dose of investigational product | PMC10667099 | ||
Other exclusions |
were investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family was defined as a spouse, parent, child or sibling, whether biological or legally adopted.were Lilly employeesThis study is registered with ClinicalTrials.gov, | PMC10667099 | ||
Lead-in period | Eligible participants were enrolled in a 12-week intensive lifestyle intervention lead-in period. The lead-in lifestyle intervention included frequent in-person lifestyle counseling sessions (that is, eight sessions over 12 weeks), delivered by a dietitian or similarly qualified healthcare professional. Women were instructed to consume approximately 1,200 kcal per day and men 1,500 kcal per day. The dietary intervention could include up to two meal replacements (liquid meal replacements or prepackaged, portion-controlled meals) per day. Participants were encouraged to engage in at least 150 min of moderate-intensity physical activity per week (for example, brisk walking). They were counseled on behavior modification strategies to help implement and adhere to the diet and exercise recommendations, and were encouraged to complete 3-day diet and exercise logs before each counseling visit. | PMC10667099 | ||
Randomization for the double-blind treatment period | weight reduction | Participants who achieved ≥5.0% weight reduction at the end of the 12-week lead-in period were randomly assigned in a 1:1 ratio to receive either the MTD of tirzepatide (10 or 15 mg) or placebo. Assignment to treatment group was determined by a computer-generated random sequence using a validated interactive web-response system. All participants, investigators and the sponsor were masked to treatment assignment. To maintain masking of participants and site staff, the single-dose pens were identical between active product and placebo. Randomization was stratified according to country, sex (female, male) and per cent weight reduction at the end of lead-in (<10 versus ≥10%). | PMC10667099 | |
Procedures during the double-blind treatment period | gastrointestinal symptoms | Tirzepatide and matched placebo were administered once weekly as a subcutaneous injection using a single-dose pen. The starting dose of tirzepatide was 2.5 mg, increasing by 2.5 mg every 4 weeks until an MTD dose of 10 or 15 mg was reached. To optimize tolerability and adherence, gastrointestinal symptoms could be managed by dietary counseling, symptomatic medications according to the investigator’s discretion or skipping of a single dose of treatment. During the first 24 weeks of the treatment period, if these mitigations were not successful one cycle of tirzepatide dose de- and re-escalation (in 2.5 mg increments) was allowed for participants unable to tolerate any dose between 7.5 and 15 mg inclusive; participants unable to tolerate 2.5 or 5 mg were discontinued from study drug but remained in the study for continued follow-up. Participants who did not tolerate up to 10 mg even after one de- and re-escalation attempt were discontinued from study drug but remained in the study for continued follow-up. Dose adjustments were not permitted after the first 24 weeks of treatment.Throughout the postrandomization period, participants continued to consult with a dietitian or other qualified healthcare professional. Lifestyle counseling sessions occurred every 12 weeks and focused on consumption of a healthy balanced diet, with a 500 kcal per day deficit and continuation of physical activity. Use of the diet and exercise log was encouraged. In between counseling sessions, diet and exercise goals were reinforced by site staff at every monthly visit.Participants were permitted to use concomitant medications that they required during the study, except for certain agents specified in the protocol that could interfere with the assessment of efficacy and safety characteristics of the study treatments. | PMC10667099 | |
Study outcomes | 72.Additional, treatment-emergent adverse, deaths, weight loss | ADVERSE EVENTS, EVENTS, SECONDARY, ACUTE PANCREATITIS | Coprimary endpoints were per cent change in body weight and the proportion of study participants who achieved ≥5% weight reduction from randomization to week 72. Key secondary endpoints, controlled for type 1 error rate, included the proportion of study participants who achieved ≥10, ≥15 or ≥20% weight reduction from randomization to week 72. The proportion of study participants who achieved ≥25% reduction in body weight was a prespecified exploratory endpoint. Key secondary endpoints also included the proportion of participants who, at week 72, maintained ≥80% of the body weight loss achieved during the 12-week lead-in period, as well as change in waist circumference (cm) from randomization to week 72.Additional secondary endpoints included change in anthropometrics (absolute body weight and BMI), cardiometabolic risk factors (blood pressure, lipids, fasting glucose, HbAIn addition, changes in the intensity of antihypertensive and lipid-lowering therapies in the double-blind period, as reported by the investigator, were assessed as prespecified exploratory endpoints.Safety endpoints included treatment-emergent adverse events and serious adverse events that occurred during the reporting period. Major adverse cardiovascular events, acute pancreatitis and deaths were reviewed by an independent external adjudication committee. | PMC10667099 |
Statistical analysis | ICH, weight reduction | REGRESSION, EVENTS, SECONDARY | A sample size of 600 participants provided power of >90% to demonstrate the superiority of tirzepatide MTD to placebo, for the coprimary endpoints, each at a two-sided significance level of 0.05. Sample size calculation assumed a difference of at least 12% in mean per cent weight reduction from randomization to week 72 for tirzepatide MTD as compared with placebo, a common s.d. of 10% and a dropout rate of 25%. Efficacy and safety endpoints were analyzed with data from all randomly assigned participants who took at least one dose of study drug (modified intention-to-treat population).Two estimands (TRE and efficacy) were used to assess treatment efficacy from different perspectives and accounted for intercurrent events differently.The TRE uses a treatment policy strategy to handle intercurrent events (ICH E9(R1)) and is intended to give an estimation of the average treatment effect of tirzepatide relative to placebo for all participants who had undergone randomization, regardless of treatment adherence. For estimation for this estimand, the intercurrent events and resulting missing values were handled by a hybrid approach using retrieved dropouts imputation from the same treatment group or using all nonmissing data assuming missing at random. This estimand is therefore also referred to as a ‘hybrid’ estimand in the study protocol. Continuous endpoints were analyzed using an analysis of covariance model, and categorical endpoints were analyzed by logistical regression. Both models included randomized treatment and stratification factors (country/pooled country, sex and per cent body weight reduction at the end of lead-in (<10 and ≥10%) as fixed effects, and baseline measure as a covariate. Analyses were conducted with hybrid imputation of missing body weight at 72 weeks and statistical inference over hybrid imputation of missing data guided by RubinSpecifically, for missing data solely due to COVID-19, missing data were considered as missing at random and imputed using all available nonmissing data of the outcome measurement from the same treatment arm; for missing data due to other intercurrent events, these were imputed based on retrieved dropouts in the same treatment arm, defined as observed primary outcome measurements, from participants in the same treatment group, who had their efficacy assessed after early discontinuation of the study drug.The efficacy estimand uses a hypothetical strategy to handle intercurrent events (ICH E9(R1)) and represented the average treatment effect of tirzepatide relative to placebo, before treatment discontinuation, for all participants who had undergone randomization. The resulting missing values (unobserved, discarded) after treatment discontinuation were implicitly handled using a mixed model for repeated measures (MMRM) under the assumption of missing at random. Continuous endpoints were analyzed using a MMRM model, and categorical endpoints by logistical regression. MMRM analysis included randomized treatment, visit, treatment-by-visit interaction and stratification factors (country/pooled country, sex and per cent body weight reduction at the end of lead-in (<10 and ≥10%) as fixed effects, and baseline measure as a covariate. The logistical regression model included randomized treatment, the same stratification factors as fixed effects and baseline measure as a covariate. Missing values were imputed by the predicted value from the MMRM model above, and continuous measurements were then dichotomized to binary outcomes. The type 1 error rate was controlled at a level of 0.05 within each estimand for evaluation of primary and key secondary objectives.Statistical analyses were carried out using SAS v.9.4, unless otherwise specified. | PMC10667099 |
Reporting summary | Further information on research design is available in the | PMC10667099 | ||
Online content | Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02597-w. | PMC10667099 | ||
Supplementary information |
List of investigators, protocol and statistical analysis plan.Reporting Summary | PMC10667099 | ||
Extended data | PMC10667099 | |||
Body weight in kg over time. | Mean (standard error) body weight (kg) over time from randomization to 72 weeks derived from a mixed-model for repeated measures (MMRM) analysis for the efficacy estimand. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. MTD, maximum tolerated dose (10 or 15 mg).
| PMC10667099 | ||
Blood pressure change from start of lead-in period over time. | Panel A, mean (95% confidence interval) change from baseline over time in systolic blood pressure from start of intensive-lifestyle intervention lead-in period (week -12) to 72 weeks using observed means. Week 72 estimates for the efficacy estimand (EFF) are also shown. Panel B, mean (95% confidence interval) change from baseline over time in diastolic blood pressure from start of intensive-lifestyle intervention lead-in period (week -12) to 72 weeks using observed means. Week 72 estimates for the efficacy estimand (EFF) are also shown.
| PMC10667099 | ||
Incidence of nausea, vomiting, and diarrhea over time. | diarrhea, nausea, vomiting | EVENTS | The percentage of participants receiving tirzepatide or placebo who reported nausea, vomiting, or diarrhea are presented. Percentages are based on number of participants at risk at specific observation time. Events were classed as mild (shown in green), moderate (shown in orange), or severe (shown in red). MTD, maximum tolerated dose (10 or 15 mg); TZP, tirzepatide.
| PMC10667099 |
Extended data | is available for this paper at 10.1038/s41591-023-02597-w. | PMC10667099 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02597-w. | PMC10667099 | ||
Acknowledgements | We, and Eli Lilly and Company, thank the clinical trial participants and their caregivers, as well as the clinical trial investigators (listed in | PMC10667099 | ||
Author contributions | N.N.A., M.C.B. and S.Z. contributed to the study design. T.A.W., A.M.C., S.M., G.S. and B.H. conducted the trial and collected data. J.C. and S.Z. were responsible for statistical analyses. S.Z., J.C., N.N.A., M.C.B. and T.F. are the guarantors of this work and, as such, take responsibility for the integrity of the data and the accuracy of data analysis. All authors participated in data interpretation, manuscript writing (assisted by a medical writer paid for by the funder) and critical review of the manuscript, had full access to all the data in the study and approved the submission of this manuscript for publication. | PMC10667099 | ||
Peer review | PMC10667099 | |||
Data availability | Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data have been made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report and blank or annotated case report forms, will be provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at | PMC10667099 | ||
Competing interests | Obesity, Nordisk and Boehringer, Nordisk | OBESITY | T.A.W. reports grants or contracts from Novo Nordisk, Epitomee Medical Co. and Eli Lilly and Company; and service on Scientific Advisory Boards for Novo Nordisk and WW. A.M.C. reports grants or contracts from National Institutes of Health, WW International, Inc, The Edna G. Kynett Memorial Foundation, Novo Nordisk and Epitomee Medical; consulting fees from Eli Lilly and Company and Boehringer Ingelheim; and payment or honoraria for presentation and travel/meeting support from the Obesity Medicine Association. S.M. reports grants or contracts from Boehringer Ingelheim, Rhythm Pharmaceuticals and Novo Nordisk; consulting fees from Novo Nordisk, Rhythm Pharmaceuticals and Eli Lilly and Company; payment or honoraria from Columbia University Medical Center, Boston Obesity Course in Obesity medicine and Medical College of Wisconsin; and participation on Advisory Boards for Novo Nordisk and Eli Lilly and Company. R.K. reports participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly and Company, Novo Nordisk and Boehringer Ingelheim. J.A. reports grants or contracts from Nestle Healthcare Nutrition, Eli Lilly and Company, Boehringer Ingelheim, Epitomee, Inc., UnitedHealth Group R&D, KVK Tech and WW; consulting fees from Nestle Healthcare Nutrition, Eli Lilly and Company, Optum Labs R&D, Novo Nordisk, Spokes Health, Inc., Intuitive, Regeneron, Brightseed, Level2 and WW; receipt of equipment, materials, drugs, medical writing, gifts or other services from KVK Tech, WW and Nestle Healthcare Nutrition; and is President Elect of The Obesity Society and an Executive Board Member of the American Society for Nutrition Foundation. G.S. reports consulting fees from Rhythm Pharmaceuticals, Novo Nordisk and Eli Lilly and Company; and speaker’s bureau from Novo Nordisk. B.H. reports payment or honoraria from Eli Lilly and Company, Novo Nordisk, Merck S.A., Astra Zeneca and Abbott Nutrition; travel/meeting support from Novo Nordisk; participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly, Novo Nordisk and Merck S.A; receipt of equipment, materials, drugs, medical writing, gifts or other services from Eli Lilly and Company and Novo Nordisk; and is President of the Brazilian Association of Obesity and a Member of Board of Trustees of World Obesity Federation representing Latin America. S.Z., J.C., M.C.B., N.N.A. and T.F. are employees and shareholders of Eli Lilly and Company. | PMC10667099 |
References | PMC10667099 | |||
Background | There is a consistent demand for implementation science to inform global efforts to close the gap between evidence and practice. Key evaluation questions for any given implementation strategy concern the assessment and understanding of effects. Randomised trials are generally accepted as offering the most trustworthy design for establishing effectiveness but may be underused in implementation science. | PMC10428627 | ||
Main body | There is a continuing debate about the primacy of the place of randomised trials in evaluating implementation strategies, especially given the evolution of more rigorous quasi-experimental designs. Further critiques of trials for implementation science highlight that they cannot provide ‘real world’ evidence, address urgent and important questions, explain complex interventions nor understand contextual influences. We respond to these critiques of trials and highlight opportunities to enhance their timeliness and relevance through innovative designs, embedding within large-scale improvement programmes and harnessing routine data.Our suggestions for optimising the conditions for randomised trials of implementation strategies include strengthening partnerships with policy-makers and clinical leaders to realise the long-term value of rigorous evaluation and accelerating ethical approvals and decluttering governance procedures for lower risk studies. | PMC10428627 | ||
Conclusion | Policy-makers and researchers should avoid prematurely discarding trial designs when evaluating implementation strategies and work to enhance the conditions for their conduct. | PMC10428627 | ||
Keywords | PMC10428627 | |||
Background | Gaps between evidence and practice pervade different healthcare systems and specialties [These research-to-practice gaps represent a strategically important problem for policy-makers, healthcare systems and research funders because they limit the health, social and economic impacts of research [There are key evaluation questions of interest to patients, professionals and policy-makers for any given implementation strategy. Does it work? For which contextual features and targeted behaviours is it likely to work? Are the costs worth the benefits?Well-conducted randomised controlled trials offer a ‘fair test’ of effectiveness by balancing known and unknown confounders so that differences in outcomes between comparison groups can be confidently attributed to intervention effects. Given that implementation strategies usually target organisations, cluster randomisation (e.g. of general practices or hospitals) is usually more appropriate than individual patient randomisation [We respond to critiques of trials for implementation science and highlight opportunities to enhance their design, delivery and efficiency. We suggest that policy-making and research communities work to optimise the conditions for conducting trials. | PMC10428627 | ||
Main text | PMC10428627 | |||
Critiques of trials | PMC10428627 | |||
Alternative evaluation designs offer similar protections against bias | ’ | There are natural, human tendencies to look for expected or even hoped for intervention effects, and hence reach erroneous conclusions from an evaluation. Comparisons of more and less rigorous evaluation methods suggest that the best way to show that an intervention ‘works’ is to use a weak non-randomised (quasi-experimental) study design without a concurrent control group [Whilst relatively sophisticated quasi-experimental designs hold considerable promise, further experience is needed to understand their properties, strengths and limitations in much the same way that it has taken decades to develop evidence-informed criteria to judge the validity and generalisability of trials [The understanding of known and unknown confounders within the context of healthcare systems is relatively poor compared to, say, biological systems. Multiple contextual influences on the outcomes of implementation strategies [Confident attribution is important given that the observed effect sizes of implementation interventions can be small, even if worthwhile from population perspectives. For example, a trial of a multifaceted implementation strategy found just over a 1% absolute difference in high-risk prescribing between intervention and control general practices, which translated into a cost-effective population benefit from reduced patient harm [ | PMC10428627 | |
Trials cannot provide ‘real world’ evidence | Clinical trials are dogged by the criticism that they recruit highly selected participants atypical of wider patient populations who may also receive above average attention, thereby limiting generalisability [ | PMC10428627 | ||
Trials cannot address urgent and important questions | fever, swallowing dysfunction, cancer deaths, hyperglycaemia, deaths, acute stroke, strokes | HYPERGLYCAEMIA, ACUTE STROKE, STROKES | Almost every healthcare problem, such as avoidable cancer deaths and strokes or maximising COVID vaccination coverage, demands urgent solutions. The history of medicine is littered with obsolete clinical recommendations based on partial evidence and assumptions, subsequently overturned by rigorous studies [Alternative evaluation designs offer the attraction of faster turnaround times than trials, with shorter planning and follow-up periods. However, time series designs depend upon stable data being available over lengthy periods. Some of the long timelines associated with implementation trials are related to burdensome research regulation and management [Well-conducted trials can overturn conventional wisdom whilst positive quasi-experimental studies may fail to convince. A trial of a multidisciplinary intervention targeting evidence-based management of fever, hyperglycaemia and swallowing dysfunction in acute stroke units found significant reductions in patient deaths or dependency at 90 days [ | PMC10428627 |
Trials shed little light on complex interventions | There are challenges in evaluating complex interventions, which contain several interacting components and target one or more behaviours, target more than one group or organisational level, result in different numbers and types of outcome and permit degrees of tailoring or flexibility [It has been suggested that whilst randomised trials may be appropriate for clinical interventions, ‘service innovations are even more complex, and this complexity needs to be embraced, not eliminated’ [Some complex interventions are not ready for trial evaluation. The UK Medical Research Council framework for the development and evaluation of complex interventions recommends the use of multiple research methods, with scope for embedding trials within a broader programme of studies which can also contribute to understanding mechanisms of change [ | PMC10428627 | ||
Trials shed little light on contextual influences | Contextual factors can have major influences on intervention effects. A criticism of trials is that by controlling for and ‘eliminating’ the influences of contextual factors, trials cannot provide information about their impacts on change [ | PMC10428627 | ||
Innovations and opportunities | PMC10428627 | |||
Identifying and prioritising ‘best bet’ interventions | Implementation interventions typically have several components but conducting multiple trials of every permutation can be wasteful. For example, varying only five elements of audit and feedback (e.g. differing frequencies of feedback) produces 288 combinations—not allowing for replication of studies or the addition of other interventions, such as educational meetings or outreach visits [The Multiphase Optimization Strategy (MOST) offers a methodological approach for building, optimising and evaluating multicomponent interventions. MOST comprises three steps: preparation, laying the groundwork for optimisation by conceptualising and piloting components; optimisation, conducting trials to identify the most promising single or combined intervention components; and evaluation, a definitive randomised trial to assess intervention effectiveness [The Sequential Multiple Assignment Randomized Trial (SMART) allows identification of the best tailoring variables and uses decision rules for adaptive interventions based upon early findings. It is especially suited for building time-varying adaptive interventions. It has been used to tailor the intensity of an intervention to improve uptake of a re-engagement programme for patients with serious mental illness according to site characteristics and initial responses to interventions [The stepped wedge design offers a solution where there is uncertainty, but randomisation to a non-intervention control is unacceptable. It entails introducing an intervention to groups of clusters in a random order. There are no ‘losers’ because all sites eventually receive the intervention. A stepped wedge trial demonstrated that an intervention comprising professional education, informatics to facilitate review and financial incentives reduced high-risk prescribing in general practices [ | PMC10428627 | ||
Implementation laboratories | cancer or stroke, cerebral palsy, Cerebral Palsy | CEREBRAL PALSY, PREMATURE DELIVERY, CEREBRAL PALSY | Trials offer opportunities to optimise the effectiveness of existing implementation interventions, in much the same way that clinical research has continually pushed marginal gains in the effective management of conditions such as cancer or stroke. Yet, establishing the infrastructure for each new trial can be costly and time-consuming. There are opportunities for implementation researchers to learn from and adapt methodologies from clinical fields, such as oncology; innovations such as ‘master protocols’ are based upon a single overarching design to evaluate multiple hypotheses with the goal of improving efficiency and standardising the development and evaluation of different interventions [Large-scale programmes offer opportunities for embedded trials. The PRevention of Cerebral Palsy in Pre-Term labour (PReCePT) programme aimed to reduce cerebral palsy by promoting the use of magnesium sulphate in pregnant women at risk of premature delivery in England. The programme included a nested trial comparing two approaches to quality improvement [The next evolutionary step is to create a learning health system which makes small, incremental changes supported by tightly focused evaluations, and thereby cumulatively improves patient care whilst developing the underpinning evidence base. Such ‘radical incrementalism’ offers a potentially cost-effective if under-utilised approach to embedding learning within large scale improvement programmes [Implementation laboratories several further advantages. First, they can reduce research waste [ | PMC10428627 |
Harnessing routinely collected data | ’ | ADVERSE EVENTS | The collection and analysis of project–specific data is expensive and limits the volume and duration of data collection. Routinely collected data can be applied to develop quality indicators [Trials using routinely collected data may also be able to achieve relatively large sample sizes, hence bolstering statistical power to detect modest effect sizes and explore effect modifiers. However, larger samples may be needed to compensate for additional ‘noise’ from using data not originally intended for research. It is important to ensure that any routinely available data are a good fit for the outcomes of interest or based upon reasonable assumptions about relevance. Using unplanned hospital readmission rates in evaluating interventions to improve the process of hospital discharge to patient homes assumes that most such readmissions are driven by adverse events and would rather be avoided by patients and healthcare systems. Just as innovative ‘platform trials’ have been crucial to guide the clinical treatment of COVID-19 [ | PMC10428627 |
Optimising conditions for trials | Increasing burdens of research regulation and management may have unwittingly conspired to undermine the feasibility and timeliness of trials [Suggestions for optimising the conditions for randomised trials of implementation strategies | PMC10428627 | ||
Authors’ contributions | All authors have been involved in the conception and drafting of the paper and have approved the final version. RF led the drafting of the paper and is guarantor. | PMC10428627 | ||
Funding | Wilson | Robbie Foy is the Implementation Laboratory lead for the National Institute for Health and Care Research (NIHR) Yorkshire and Humber Applied Research Collaboration. Paul Wilson is the Implementation Science research theme lead for the NIHR Greater Manchester Applied Research Collaboration. This report is independent research funded by the NIHR Yorkshire and Humber Applied Research Collaboration (NIHR 200166) and the NIHR Greater Manchester Applied Research Collaboration. The views expressed in this publication are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.Noah Ivers holds a Canada Research Chair in Implementation of Evidence-based Practice. Jeremy Grimshaw holds a Canada Research Chair in Health Knowledge Transfer and Uptake. | PMC10428627 | |
Availability of data and materials | Not applicable. | PMC10428627 | ||
Declarations | PMC10428627 | |||
Ethics approval and consent to participate | Not applicable. | PMC10428627 | ||
Consent for publication | Not applicable. | PMC10428627 | ||
Competing interests | Wilson | Robbie Foy, Noah Ivers and Jeremy Grimshaw are members of the Audit and Feedback MetaLab. The MetaLab is an international collaboration to advance learning and expertise on Audit and Feedback and promotes the development of audit and feedback implementation laboratories internationally. Paul Wilson is Co-Editor in Chief of Implementation Science, and Robbie Foy, Noah Ivers and Jeremy Grimshaw are Editorial Board members. | PMC10428627 | |
References | PMC10428627 | |||
Background | Acupuncture, allergic rhinitis | ALLERGIC RHINITIS | Acupuncture is used to treat allergic rhinitis (AR) in traditional Chinese medicine, and the ST2 and ST36 acupoints are generally selected in clinical practice. We report a new intranasal acupuncture method at the Neiyingxiang (EX-HN9) and Biqiu points for the treatment of persistent AR (PAR). Here, the efficacy and safety of this method were evaluated. | PMC10175315 |
Methods | ADVERSE EVENTS, SECONDARY, RHINOCONJUNCTIVITIS | A total of 120 patients diagnosed with PAR were randomly allocated (2:1 ratio) to intranasal acupuncture or Western medicine groups, the basic principle of random grouping is SAS random grouping method. The applicator held a nasal endoscope and a 0.30 × 75 mm filiform needle in their left and right hands, respectively. When aiming at the Neiyingxiang or Biqiu point, the applicator quickly inserted the needle to a 20-mm depth as parallel as possible to the inferior turbinate or middle turbinate, without special reinforcing and reducing techniques (the needle remained for 20 min). The intranasal acupuncture groups received acupuncture treatment three times per week for 2 weeks. The Western medicine group was treated with budesonide nasal spray (two sprays/nostril, twice/day) and loratadine (one tablet/night) for 2 weeks. Visual analog scale (VAS) scores were the primary outcome. Quality of life, medication dosages and adverse events were secondary outcomes measured using the Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ). Confidence assessments were performed to evaluate data from the treatment and follow-up periods. | PMC10175315 | |
Results | The results were as follows: (1) VAS and RQLQ scores were significantly lower in the intranasal acupuncture group than in the Western medicine group on day 1 (i.e., first treatment) ( | PMC10175315 | ||
Conclusions | nasal congestion | Intranasal acupuncture has good efficacy and safety in the treatment of PAR. Moreover, VAS and RQLQ scores were much lower in the intranasal acupuncture group than in the Western medicine group, and acupuncture had an immediate impact, especially for improving nasal congestion, olfactory function and sleep. | PMC10175315 | |
Keywords | PMC10175315 | |||
Background | itching, rhinorrhea, respiratory allergic disease, Allergic rhinitis, Acupuncture, nasal blockage, rhinitis | ADVERSE EFFECTS, RHINITIS, ALLERGIC RHINITIS, CAVITY | Allergic rhinitis (AR) is a chronic respiratory allergic disease mediated by IgE that is characterized by the clinical symptoms of sneezing, itching, rhinorrhea and nasal blockage. It affects 10–40% of the population, approximately one billion people worldwide [Currently, conventional medical treatment can effectively relieve AR symptoms. However, there is still poor clinical efficacy in some patients and adverse effects of these medications. Although no comprehensive assessment of their antiallergic–rhinitis mechanisms has been published, and scientific results have yet been undertaken, traditional Chinese medicine (TCM) herbs are beneficial against AR [Acupuncture is a widely used and relatively safe nonpharmacological treatment for some conditions. It is gradually becoming an important complementary and alternative strategy for the treatment of AR [We have applied a novel and alternative therapy for PAR via intranasal acupuncture (IA) in the clinic and achieved good effects. IA is a treatment involving the needling of specific areas (Neiyingxiang (EX-HN9) and Biqiu points) in the nasal cavity (Fig. Schematic diagram of intranasal acupuncture (When aiming at the Neiyingxiang or Biqiu point, the applicator quickly inserted the needle to a 20-mm depth as parallel as possible to the inferior turbinate or middle turbinate, without special reinforcing and reducing techniques (the needle remained for 20 min). | PMC10175315 |
Methods/design | PMC10175315 | |||
Ethical statement | The study was conducted in accordance with the Declaration of Helsinki Good Clinical Practice guidelines. It was approved by the Institutional Review Boards of Beijing University of Chinese Medicine (approval number BZYYYDX-LL-20150208), which is a central ethics committee providing approval for our center. Written informed consent was acquired from all participants. | PMC10175315 | ||
Trial design | Acupuncture, nasal congestion | ADVERSE EVENT, RHINOCONJUNCTIVITIS, EAR, SECONDARY, NOSE | In the clinical pre experiment of the research group, the nasal symptoms (especially nasal congestion) of patients were significantly improved after acupuncture for 3 times. When acupuncture for 7 times, the curative effect reached a stable stage. We designed a single center trial that randomly assigned patients to 2 weeks of IA or Western medicine treatment, and we assessed visual analog scale (VAS) scores as main outcomes and Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ) scores as secondary measurements at the end of the first treatment (1 day), at the end of treatment (2 weeks), and 4 weeks after treatment (at 6 weeks) (Fig. Study design. The study was conducted at the Department of Ear, Nose and Throat (ENT) in the Dongzhimen Hospital Beijing University of Chinese Medicine in China. In this study, the patients were guided to stop taking anti-allergy medications for at least 7 days. After completing the baseline assessment, the patients were randomized into either the intranasal acupuncture group (IAG) or Western medicine group (WMG) and received 2 weeks of IA treatment (because intranasal acupuncture has a direct stimulative effect on the nasal mucosa, it needs self-healing of the mucosa after acupuncture. Acupuncture is selected every other day for a total of 7 times, so the treatment course are 2 weeks) or budesonide nasal spray combined with loratadine tablets (Western medicine). The patients completed all primary and secondary measures at baseline, 2 weeks and 6 weeks. Adverse events were identified during intervention sessions and follow-up interviews. | PMC10175315 |
Participants | sinusitis, congenital nasal abnormalities, rhinorrhea, liver or kidney dysfunction, active pulmonary tuberculosis, anemia, nasal dermoid cysts, nasal obstruction, nasal itching, asthma, sneezing | ALLERGY SKIN, UNCONTROLLED HYPERTENSION, SYSTEMIC DISEASE, SINUSITIS, ANEMIA, ALLERGIC RHINITIS, ASTHMA, ASTHMA, MALIGNANT TUMOR, INACTIVE PULMONARY TUBERCULOSIS, INSULIN-DEPENDENT DIABETES MELLITUS, DYSLIPIDEMIA | The eligible participants were older than 18 years and met the criteria of moderate to severe PAR, according to the criteria listed in “Allergic Rhinitis and its Impact on Asthma (ARIA)” [The inclusion criteria included symptoms that had persisted for more than 4 days per week for more than four consecutive weeks and at least one of the following rhinitis-associated conditions: nasal obstruction, rhinorrhea, sneezing, and nasal itching. All included participants exhibited at least one positive result on an allergy skin prick reaction test at screening. All participants had a certain degree of drug resistance to glucocorticoids in the past. The participants were excluded if they suffered from serious medical conditions, such as uncontrolled hypertension, insulin-dependent diabetes mellitus, past or current malignant tumor, severe dyslipidemia, liver or kidney dysfunction, anemia, active pulmonary tuberculosis, or other infectious or systemic diseases that would make treatment with acupuncture inappropriate. Participants were deemed ineligible if they suffered from congenital nasal abnormalities, including nasal dermoid cysts and congenital midline nasal masses, sinusitis, or asthma or deviation of nasal septum; had a history of nose surgery; had received CAM therapy for AR within the previous 6 months; or had received systemically administered corticosteroids, antihistamines, or decongestants within 6 months prior to enrollment. During acupuncture, we usually use nasal endoscopy for auxiliary treatment, and do not use local anesthesia spray to promote needle insertion. | PMC10175315 |
Randomization and interventions | CAVITY, RECRUITMENT | A total of 120 eligible patients were recruited and were randomly assigned at a 2:1 ratio to the IAG or WMG. Randomization sequences were generated using SAS software (SAS Institute Inc., Cary, NC, USA). Random numbers were concealed using sequentially numbered, opaque, sealed envelopes by an independent researcher who was not involved in the clinical trial. The doctors and participants in the IAG and WMG could not be blinded to the treatment assignments given the nature of the interventions. Outcome assessors, data collectors, and statisticians were blinded to the treatment allocation. Due to the time limit of recruitment (March 2018 December 2019), patients with PAR mostly seek a variety of traditional Chinese medicine alternative treatment, and there are fewer patients treated with intranasal acupuncture alone or Western medicine alone, resulting in a relatively insufficient sample size.We developed the trial interventions in a consensus process with experienced acupuncture experts. In the IAG, participants received 7 treatments, that is, once every other day for 2 weeks. The acupuncture sites for IA treatment were selected to be Neiyingxiang (EX-HN9) and Biqiu points in the bilateral nasal cavity (Fig. According to the guidelines for the treatment of AR recommended by ARIA in 2016 [Study flow diagram. | PMC10175315 | |
Outcome measurements | The primary outcomes were VAS scores for nasal symptoms. The scale includes overall nasal symptoms and differentiated nasal symptoms. The highest score for each section is 10, which represents a symptom that is unbearable; the lowest score for each section is 0, which represents a symptom with no influence.Secondary outcomes were measures of participant quality of life, which were assessed with the RQLQ [ | PMC10175315 | ||
Statistical analysis | The statistical analysis was performed using the SPSS statistical software system (SPSS Inc., Chicago, IL; version 22.0). Data are represented as means and standard deviations. Nonparametric tests were used for comparisons across groups for pretreatment and posttreatment data that were not normally distributed. Intragroup comparisons were performed using paired t tests or Wilcoxon rank-sum tests. Two-tailed | PMC10175315 |
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