Completeness of intervention reporting in randomised trials of technology-enabled remote or hybrid exercise-based cardiac rehabilitation: a systematic review using the TIDieR framework.

BACKGROUND: Exercise-based cardiac rehabilitation improves clinical outcomes and quality of life. Technology-enabled delivery of remote cardiac rehabilitation is as effective in improving health outcomes as in-person delivery and has the potential to transform clinical service delivery. However, for the successful translation of research to clinical practice, interventions must be adequately reported in the literature. METHODS: Systematic review of MedLine, CINAHL, PubMed and SPORT Discus databases applying PRISMA guidance. Randomised controlled trials of remote or hybrid technology-enabled exercise-based cardiac rehabilitation interventions were included. Completeness of reporting was evaluated against the TIDieR checklist. RESULTS: The search strategy returned 162 articles which, following screening, resulted in 12 randomised trials being included containing data for 1588 participants. No trial fully reported their rehabilitation intervention as per the 12-item TIDieR checklist, with a median score of eight out of 12 categories. Notably, intervention detail, dosage and modification were comparatively poorly reported. CONCLUSION: Technology-enabled remotely delivered cardiac rehabilitation may be effective at improving cardiovascular fitness; however, the quality of reporting of these interventions in randomised trials is insufficient for replication which has material implications for translation into clinical practice.

Underrecording and underreporting of participant ethnicity in clinical trials is persistent and is a threat to inclusivity and generalizability.

OBJECTIVES: People from ethnic minority groups are underserved by randomized trials, and poor representation of these groups reduces generalizability of results. There is no guidance on which ethnicity categories are appropriate for use in trials and thus inconsistency exists. The purpose of this study is to establish, in a large sample of trials, if participant ethnicity is recorded, how it is obtained (categories used), and if its reporting varies from its recording. STUDY DESIGN AND SETTING: We reviewed trial documentation for 407 randomized controlled trials published in the UK National Institute of Health Research library from 2016 to 2021. We extracted data on the recording (if it was recorded and the categories used) and reporting (if the categories remained the same as those obtained, or not) of ethnicity for each trial along with demographics. In the analysis we categorized the manner of recording and reporting of ethnicity in the trials according to UK Census ethnicity categories. RESULTS: Ethnicity was recorded in 67.3% (n = 274) of trials. The location in the trial report where ethnicity was recorded was available for 42% (n = 116) of trials. The details on how ethnicity was collected (predefined categories or self-defined) was available for 54/274 (20%) of trials and details on the specifics of the categories recorded was available for 44 (16%) trials. Of the 44, 6 of those did not go on to report on ethnicity in the trial report. Of the remaining 38, only 13 reported ethnicity exactly as it had been recorded. Taken as a whole from the 407 trial reports examined 9.3% (38/407) of trials demonstrated exactly how they both recorded, and reported, ethnicity. Authors made reference to whom results were relevant in terms of ethnicity in 80/407 (19.7%). CONCLUSION: Ethnicity is underrecorded and underreported in clinical trials. This is a threat to the generalizability of the findings and needs to be improved.

Comparison of Spinal Cord Stimulation Trial Reporting Protocols and Long-Term Pain Relief Outcomes Following Implantation.

OBJECTIVES: Appropriate spinal cord stimulation (SCS) candidates are required to undergo an SCS trial before implant, typically with ≥50% pain relief deemed "successful." However, SCS trialing protocols can vary substantially. The primary aim of this retrospective study is to investigate the associations between SCS trial results and long-term SCS pain outcomes. MATERIALS AND METHODS: This study was a retrospective single-center review of successful SCS trials from January 1, 2017, to July 1, 2019. A total of 115 patients were included. Group differences in continuous variables were evaluated using t-tests, and group differences in categorical variables were evaluated using the χ2 test. The percentage improvement in long-term pain intensity was analyzed as a binary variable, where long-term success was defined as ≥50% improvement in numeric rating scale pain scores. The level of significance for all tests was set at p < 0.05. RESULTS: The mean age was 64.9 years, and 52% of patients were men. The mean pain score at long-term follow-up was 4.7 ± 2.6, and the median time from implantation to follow-up was 13 months (25th-75th interquartile range; 4-22). In the logistic regression analysis adjusted for age, sex, and follow-up time, greater patient-reported percentage improvement in pain scale during the trial was significantly associated with greater odds of experiencing ≥50% improvement in pain scores (p = 0.048; 95% CI 1.00-1.70). All other assessed trial metrics were not significantly associated with greater odds of experiencing >50% improvement in pain scores at last follow-up. CONCLUSIONS: Given the variability in current assessment techniques, we recommend the patient-reported percentage improvement in pain scale as the posttrial assessment method of choice instead of a calculated percentage improvement. However, our results indicate that current trial assessment methods are generally poor, and improved trial reporting protocols must be sought.

Sex and Gender in Randomized Controlled Trials of Adults Receiving Maintenance Dialysis: A Meta-epidemiologic Study.

RATIONALE & OBJECTIVE: How sex and gender concepts are incorporated into randomized controlled trials (RCTs) in adults with kidney failure receiving maintenance dialysis is largely unknown. We describe these practices in published journal articles as well as investigate the proportion of women and female participants in these studies. STUDY DESIGN: Meta-epidemiologic study. SETTING & STUDY POPULATIONS: RCTs in maintenance dialysis. SELECTION CRITERIA FOR STUDIES: Trials published in high-impact journals in 2000-2020. DATA EXTRACTION: Implemented in duplicate with conflicts resolved by a third reviewer. ANALYTICAL APPROACH: Meta-regression was performed to identify trial characteristics independently associated with the proportion of women and female participants. RESULTS: Among 561 included RCTs, 69.7% were parallel and 28.0% were crossover in design; 80.6% were conducted in the hemodialysis population; and 25% of trials compared the treatment of interest with a placebo arm, 25% with a usual care treatment arm, and 50% with an active alternative therapy arm. Of the RCTS, 37.6% were masked. The median size was 60 (IQR, 26-151) participants, and the median follow-up period was 154 (IQR, 42-365) days. The mean proportion of women or female participants was 0.40±0.13 (SD): 39.0% of trials reported sex, and 26.6% reported the gender of the participants. Also, 56.2% referred to participants as females, 25.3% referred to participants as women, and 15.5% referred to both females and women. No trial characteristic other than region (ß of 0.062 [95% CI, 0.007-0.117] for Asia) was associated with the proportion of women or female participants. Considering trial design and conduct, 2.7% of trials used sex and/or gender as an inclusion criterion, 26.6% as an exclusion criterion, 4.5% for randomization, 4.8% for subgroup analyses, and 15.7% for covariate adjustment. LIMITATIONS: Only high-impact journal articles were studied; and the included studies lacked pediatric trials, those addressing chronic kidney disease or kidney transplantation, any trials from Africa and underrepresentation of other regions, and missing data. CONCLUSIONS: RCTs in dialysis are representative of the general dialysis population with regard to sex and gender but they uncommonly report both and often do not include either in their reporting or analysis.

Issues with reporting and interpretation of Khan et al. 2021.

A recent publication in BMC Infectious Diseases concerning the use of convalescent plasma for the treatment of COVID-19 had a number of major issues. This correspondence details specific instances of unclear reporting as well as major omissions when discussing the context of the trial. These render the study's findings and conclusions misleading.

Using qualitative research to develop an elaboration of the TIDieR checklist for interventions to enhance vaccination communication: short report.

BACKGROUND: The COVID-19 pandemic has led to an increased interest in communication with the public regarding vaccination. Our recent Cochrane qualitative evidence synthesis points to several factors that could influence the implementation and success of healthcare worker communication with older adults about vaccination. However, it is often difficult to assess whether factors identified as potentially important in qualitative studies have been considered in randomized trials because of poor trial reporting. We therefore decided to use our qualitative evidence synthesis findings to encourage better reporting of vaccination communication interventions in trials by developing an elaboration of the TIDieR (Template for Intervention Description and Replication) checklist for intervention reporting. METHODS: We examined the findings from our Cochrane qualitative evidence synthesis on healthcare workers' perceptions of and experiences with communicating about vaccination with adults over the age of 50 years. We identified factors that could influence the implementation and uptake, and thereby the effectiveness, of vaccination communication interventions. We then drafted a list of the information elements we would need from trial reports to assess whether these factors had been considered in the development of the interventions evaluated in these trials. Finally, we compared our list of information elements to the TIDieR checklist items. We were able to align all of our information elements with the TIDieR items. However, for several of the TIDieR items, we developed a more detailed description to ensure that relevant information would be captured sufficiently in trial reports. RESULTS: We developed elaborations for the following TIDieR items: "Why" (item 2), "What-materials" (item 3), "Who provided" (item 5), "How" (item 6), "Where" (item 7) and "Tailoring" (item 9). CONCLUSIONS: Both qualitative research and trials of intervention effectiveness are critical to furthering our understanding of what works, where, for whom and through which mechanisms. However, a key ingredient for developing this understanding is adequate reporting of intervention design, content and implementation in randomized trials. We hope that this elaboration of the TIDier checklist will improve reporting of interventions in trials focused on vaccine communication with older adults, and thereby enhance the usability of this research for developing future communication strategies.

Evaluation of the design, conduct and reporting of randomised controlled trials in the haemodialysis population: a scoping review and interview study.

BACKGROUND: Fewer trials are conducted in nephrology than any other specialty, often failing to recruit to target, resulting in unclear evidence affecting translation to clinical practice. This mixed-methods study aims to provide guidance for designing and reporting future randomised controlled trials (RCTs) in the haemodialysis population. METHOD: A scoping review was conducted. Five databases (MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov) were searched for RCTs published between 2013 and 2019 involving prevalent adult haemodialysis patients. Reporting of sample size, recruitment, retention and statistical significance of primary outcome were assessed. Face-to-face semistructured interviews were conducted with individuals from a single centre during dialysis sessions. Interviews were analysed thematically. RESULTS: Of 786 RCTs identified, 636 (80.9%) were parallel-group, 139 (17.7%) were crossover and 11 (1.4%) were cluster (including one stepped-wedge) design. Sample size justification was reported in 73.1%, 53.8% and 45.5% of parallel-group, crossover and cluster trials, respectively.Target recruitment was achieved by 45.5% of cluster, 53.8% of crossover and 57.7% of parallel-group trials with patient retention at 75.6%, 83.1% and 87.8%, respectively. Primary outcome reached statistical significance in 81.8% of cluster trials, 69.2% of parallel-group and 38.5% of crossover trials.Themes identified from individual interviews: perceptions of the convenience of trial participation; group allocation; perceptions of the benefits and adverse effects of taking part in clinical trials. CONCLUSION: The recruitment and reporting of RCTs involving people on haemodialysis could be improved. Involvement of all stakeholders and especially participants in the trial design process may address issues around participant burden and ultimately improve the evidence base for clinical practice.

Quality of reporting of clinical trials in dogs and cats: An update.

BACKGROUND: Comprehensive reporting of clinical trials is essential to allow the trial reader to evaluate the methodological rigor of the trial and interpret the results. Since publication of the updated Consolidated Standards of Reporting Trials (CONSORT) guidelines for reporting of parallel clinical trials in humans, extensions for reporting of abstracts and crossover trials have been published. OBJECTIVES: To describe the types of trials using dogs and cats published from 2015 to 2020 and to evaluate the quality of reporting of a sample of recently published parallel and crossover trials. ANIMALS: None. METHODS: A comprehensive search was conducted to identify parallel or crossover design clinical trials using dogs and cats published from January 1, 2015 onwards. Quality of reporting was evaluated on a subset of trials published during 2019. The reporting of items recommended in the CONSORT reporting guidelines for abstracts, parallel trials, and crossover trials was evaluated independently by 2 reviewers using standardized forms created for this study. Disagreements among reviewers were resolved by consensus. Results were tabulated descriptively. RESULTS: The frequency of reporting of trial features varied from low to high. There remain deficiencies in the quality of reporting of key methodological features and information needed to evaluate and interpret trial results. CONCLUSIONS AND CLINICAL IMPORTANCE: There is still a need for authors, peer-reviewers, and editors to follow reporting guidelines such as CONSORT to maximize the value of clinical trials and to increase confidence in the validity of the trial results.

Biases in study design, implementation, and data analysis that distort the appraisal of clinical benefit and ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scoring.

BACKGROUND: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated, widely used tool developed to score the clinical benefit from cancer medicines reported in clinical trials. ESMO-MCBS scores assume valid research methodologies and quality trial implementation. Studies incorporating flawed design, implementation, or data analysis may generate outcomes that exaggerate true benefit and are not generalisable. Failure to either indicate or penalise studies with bias undermines the intention and diminishes the integrity of ESMO-MCBS scores. This review aimed to evaluate the adequacy of the ESMO-MCBS to address bias generated by flawed design, implementation, or data analysis and identify shortcomings in need of amendment. METHODS: As part of a refinement of the ESMO-MCBS, we reviewed trial design, implementation, and data analysis issues that could bias the results. For each issue of concern, we reviewed the ESMO-MCBS v1.1 approach against standards derived from Helsinki guidelines for ethical human research and guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, the Food and Drugs Administration, the European Medicines Agency, and European Network for Health Technology Assessment. RESULTS: Six design, two implementation, and two data analysis and interpretation issues were evaluated and in three, the ESMO-MCBS provided adequate protections. Seven shortcomings in the ability of the ESMO-MCBS to identify and address bias were identified. These related to (i) evaluation of the control arm, (ii) crossover issues, (iii) criteria for non-inferiority, (iv) substandard post-progression treatment, (v) post hoc subgroup findings based on biomarkers, (vi) informative censoring, and (vii) publication bias against quality-of-life data. CONCLUSION: Interpretation of the ESMO-MCBS scores requires critical appraisal of trials to understand caveats in trial design, implementation, and data analysis that may have biased results and conclusions. These will be addressed in future iterations of the ESMO-MCBS.

Do interventions to improve adherence to antiretroviral therapy recognise diversity? A systematic review.

People living with HIV (PLWH) are often culturally and linguistically diverse populations; these differences are associated with differing barriers to antiretroviral therapy (ART) adherence. Cultural competence measures the extent to which trial design recognises this diversity. This systematic review aimed to determine whether adherence trial participants represent the diversity of PLWH. Randomised Controlled Trials in Organisation for Economic Co-operation and Development countries to improve ART adherence were eligible. We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews. For all included trials, we searched for their development, testing and evaluation studies. We compared trial participant characteristics with nationally reported PLWH data. We appraised trial cultural competence against ten criteria; scoring each criterion as 0, 1 or 2 indicating cultural blindness, pre-competence or competence respectively. For 80 included trials, a further 13 studies presenting development/testing/evaluation data for the included trials were identified. Only one of the 80 included studies reported trial participants representative of the country's population of PLWH. The median (IQ) cultural competence score was 2.5 (1.0, 4.0) out of 20. HIV adherence trial participants are not reflective of the population with HIV, which may be due to limited adoption of culturally competent research methods.

Who knew? The misleading specificity of "double-blind" and what to do about it.

BACKGROUND: In randomized trials, the term "double-blind" (and its derivatives, single- and triple-blind, fully blind, and partially blind or masked) has no standard or widely accepted definition. Agreement about which groups are blinded is poor, and authors using these terms often do not identify which groups were blinded, despite specific reporting guidelines to the contrary. Nevertheless, many readers assume-incorrectly-that they know which groups are blinded. Thus, the term is ambiguous at best, misleading at worst, and, in either case, interferes with the accurate reporting, interpretation, and evaluation of randomized trials. The problems with the terms have been thoroughly documented in the literature, and many authors have recommended that they be abandoned. PROPOSAL: We and our co-signers suggest eliminating the use of adjectives that modify "blinding" in randomized trials; a trial would be described as either blinded or unblinded. We also propose that authors report in a standard table which groups or individuals were blinded, what they were blinded to, how blinding was implemented, and whether blinding was maintained. Individuals with dual responsibilities, such as caregiving and data collecting, would also be identified. If blinding was compromised, authors should describe the potential implications of the loss of blinding on interpreting the results. CONCLUSION: "Double blind" and its derivatives are terms with little to recommend their continued use. Eliminating the use of adjectives that impart a false specificity to the term would reduce misinterpretations, and recommending that authors report who was blinded to what and how in a standard table would require them to be specific about which groups and individuals were blinded.

Registration of phase 3 crossover trials on ClinicalTrials.gov.

BACKGROUND: In a randomized crossover trial, each participant is randomized to a sequence of treatments and treatment effect is estimated based on within-individual difference because each participant serves as his/her own control. This feature makes the design and reporting of randomized crossover trials different from that of parallel trials. Our objective was to characterize phase 3 crossover trials with results reported on ClinicalTrials.gov and identify issues and best practices for reporting. METHODS: We searched ClinicalTrials.gov for phase 3 randomized crossover trials that provided results, registered at least one primary outcome, and included at least one link to a results publication in the record by August 6, 2019. Two reviewers independently assessed the eligibility and extracted information from each record into an electronic form developed and maintained in the Systematic Review Data Repository. RESULTS: Of the 124 crossover trials analyzed, two thirds were a simple "Intervention A then B" or "Intervention B then A" (AB|BA) design. Most trials (78%, 97/124) provided enough information to understand the participant flow throughout the trial. Baseline characteristics were most often reported for all participants as a single group (52%, 65/124). Primary outcomes and adverse events were most commonly reported "per intervention" (85%, 105/124, and 80%, 99/124, respectively). CONCLUSIONS: The registration and reporting of randomized crossover trials must account for the paired nature of the design. Our observations and recommendations informed the development of guidelines for good reporting practices in the registration and reporting of randomized crossover trials.

Consistency of trial reporting between ClinicalTrials.gov and corresponding publications: one decade after FDAAA.

The FDA Amendments Act (FDAAA) required that information for certain clinical trials, such as details about study design features and endpoints, as well as results, be publicly reported in ClinicalTrials.gov . We conducted a cross-sectional analysis of phase III trials with primary results published between January 1, 2016, and June 30, 2017, in high-impact journals and found 74% contained at least one discrepancy between results reported in ClinicalTrials.gov and the corresponding publication. Our findings underscore the necessity for monitoring of clinical trial information and result reporting between sources; a checklist may provide a systemized procedure for investigators and editors to monitor accurate reporting.

Harmonized Outcome Measures for Use in Depression Patient Registries and Clinical Practice.

Major depressive disorder is a common mental health condition that affects an estimated 16.2 million adults and 3.1 million adolescents in the United States. Yet, a lack of uniformity remains in measurements and monitoring for depression both in clinical practice and in research settings. This project aimed to develop a minimum set of standardized outcome measures relevant to both patients and clinicians that can be collected in depression registries and clinical practice. Twenty-nine depression registries and related data collection efforts were identified and invited to submit outcome measures. Additional measures were identified through literature searches and reviews of quality measures. A multistakeholder panel representing clinicians; payers; government agencies; industry; and medical specialty, health care quality, and patient advocacy organizations categorized the 27 identified measures using the Agency for Healthcare Research and Quality's supported Outcome Measures Framework. The panel identified 10 broadly relevant measures and harmonized definitions for these measures through in-person and virtual meetings. The harmonized measures represent a minimum set of outcomes that are relevant to clinicians and patients and appropriate for use in depression research and clinical practice. Routine and consistent collection of these measures in registries and other systems would support creation of a national research infrastructure to efficiently address new questions, improve patient management and outcomes, and facilitate care coordination.

Benefits and Harms of Prescription Drugs and Supplements for Treatment of Clinical Alzheimer-Type Dementia.

BACKGROUND: Effects of drug treatment of clinical Alzheimer-type dementia (CATD) are uncertain. PURPOSE: To summarize evidence on the effects of prescription drugs and supplements for CATD treatment. DATA SOURCES: Electronic bibliographic databases (inception to November 2019), ClinicalTrials.gov (to November 2019), and systematic review bibliographies. STUDY SELECTION: English-language trials of prescription drug and supplement treatment in older adults with CATD that report cognition, function, global measures, behavioral and psychological symptoms of dementia (BPSD), or harms. Minimum treatment was 24 weeks (≥2 weeks for selected BPSD). DATA EXTRACTION: Studies with low or medium risk of bias (ROB) were analyzed. Two reviewers rated ROB. One reviewer extracted data; another verified extraction accuracy. DATA SYNTHESIS: Fifty-five studies reporting non-BPSD outcomes (most ≤26 weeks) and 12 reporting BPSD (most ≤12 weeks) were analyzed. Across CATD severity, mostly low-strength evidence suggested that, compared with placebo, cholinesterase inhibitors produced small average improvements in cognition (median standardized mean difference [SMD], 0.30 [range, 0.24 to 0.52]), no difference to small improvement in function (median SMD, 0.19 [range, -0.10 to 0.22]), no difference in the likelihood of at least moderate improvement in global clinical impression (median absolute risk difference, 4% [range, 2% to 4%]), and increased withdrawals due to adverse events. In adults with moderate to severe CATD receiving cholinesterase inhibitors, low- to insufficient-strength evidence suggested that, compared with placebo, add-on memantine inconsistently improved cognition and improved global clinical impression but not function. Evidence was mostly insufficient about prescription drugs for BPSD and about supplements for all outcomes. LIMITATION: Most drugs had few trials without high ROB, especially for supplements, active drug comparisons, BPSD, and longer trials. CONCLUSION: Cholinesterase inhibitors and memantine slightly reduced short-term cognitive decline, and cholinesterase inhibitors slightly reduced reported functional decline, but differences versus placebo were of uncertain clinical importance. Evidence was mostly insufficient on drug treatment of BPSD and on supplements for all outcomes. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897).

Room for improvement in reporting of trials discontinuing long-term medication: a systematic review.

BACKGROUND AND OBJECTIVE: Discontinuation of inappropriate medication is widely recognized as an essential component of best prescribing practice. Physicians typically attempt to taper or stop medications on the basis of clinical experience, rather than using a systematic approach guided by evidence. We sought to evaluate if the reporting of deprescribing trials conducted in primary care is of sufficient quality and detail to allow replication in clinical practice. METHODS: This study presents a secondary analysis of data from a systematic review published in 2018, investigating the effects of discontinuation of chronic medication in primary care. Twenty-six publications reporting on 27 trials were included. The quality of reporting was assessed using the Template for Intervention Description and Replication (TIDieR) checklist. RESULTS: No study provided complete reporting on all TIDieR items. All studies provided a clear description and rationale for the intervention; however, details of the intervention were insufficiently reported in most studies, with high variability between studies. Consultation of secondary sources resulted in minimal additional information. CONCLUSIONS: There are significant deficits in reporting methodological details of deprescribing interventions in primary care. It is likely that evidence-based deprescribing is not being implemented as routinely into health-care practice as it could be. Increasing the quality of intervention reporting is essential to avoid wastage of research resources and ought to be a focus for all discontinuation trials.

Proportion of published primary health care protocols with published results in subsequent papers was decreasing.

OBJECTIVES: We assessed the proportion of primary health care (PHC) randomized controlled trial (RCT) protocols published in peer-reviewed journals that published results in subsequent papers in peer-reviewed journals; and whether this proportion changed over time. STUDY DESIGN AND SETTING: We searched (last update June 2019) for RCTs published in peer-reviewed journals reporting primary outcome results for 620 protocols that were published up to 2014 and were retrieved in PubMed. We recorded the absolute number and the proportion of protocols with published results per year; and estimated whether the proportion changed over time. RESULTS: Of the 620 published protocols, 525 (85%) disseminated their results through a published RCT by June 2019. The number of published protocols was increasing over time especially after 2001. However, the proportion of protocols per year with published results in subsequent papers was decreasing over time after 2002. Specifically, the proportion ranged from 86% to 96% for protocols published until 2010 while for those published from 2011 onward ranged from 76% to 86%. Mean time from protocol to results publication was 39 months (95% CI 37, 41). CONCLUSION: Almost one-sixth of PHC trial protocols published in peer-reviewed journals did not publish their results in subsequent papers.

Are non-constant rates and non-proportional treatment effects accounted for in the design and analysis of randomised controlled trials? A review of current practice.

BACKGROUND: Most clinical trials with time-to-event primary outcomes are designed assuming constant event rates and proportional hazards over time. Non-constant event rates and non-proportional hazards are seen increasingly frequently in trials. The objectives of this review were firstly to identify whether non-constant event rates and time-dependent treatment effects were allowed for in sample size calculations of trials, and secondly to assess the methods used for the analysis and reporting of time-to-event outcomes including how researchers accounted for non-proportional treatment effects. METHODS: We reviewed all original reports published between January and June 2017 in four high impact medical journals for trials for which the primary outcome involved time-to-event analysis. We recorded the methods used to analyse and present the main outcomes of the trial and assessed the reporting of assumptions underlying these methods. The sample size calculation was reviewed to see if the effect of either non-constant hazard rates or anticipated non-proportionality of the treatment effect was allowed for during the trial design. RESULTS: From 446 original reports we identified 66 trials with a time-to-event primary outcome encompassing trial start dates from July 1995 to November 2014. The majority of these trials (73%) had sample size calculations that used standard formulae with a minority of trials (11%) using simulation for anticipated changing event rates and/or non-proportional hazards. Well-established analytical methods, Kaplan-Meier curves (98%), the log rank test (88%) and the Cox proportional hazards model (97%), were used almost exclusively for the main outcome. Parametric regression models were considered in 11% of the reports. Of the trials reporting inference from the Cox model, only 11% reported any results of testing the assumption of proportional hazards. CONCLUSIONS: Our review confirmed that when designing trials with time-to-event primary outcomes, methodologies assuming constant event rates and proportional hazards were predominantly used despite potential efficiencies in sample size needed or power achieved using alternative methods. The Cox proportional hazards model was used almost exclusively to present inferential results, yet testing and reporting of the pivotal assumption underpinning this estimation method was lacking.

Reporting non-adherence in cluster randomised trials: A systematic review.

BACKGROUND: Treatment non-adherence in randomised trials refers to situations where some participants do not receive their allocated treatment as intended. For cluster randomised trials, where the unit of randomisation is a group of participants, non-adherence may occur at the cluster or individual level. When non-adherence occurs, randomisation no longer guarantees that the relationship between treatment receipt and outcome is unconfounded, and the power to detect the treatment effects in intention-to-treat analysis may be reduced. Thus, recording adherence and estimating the causal treatment effect adequately are of interest for clinical trials. OBJECTIVES: To assess the extent of reporting of non-adherence issues in published cluster trials and to establish which methods are currently being used for addressing non-adherence, if any, and whether clustering is accounted for in these. METHODS: We systematically reviewed 132 cluster trials published in English in 2011 previously identified through a search in PubMed. RESULTS: One-hundred and twenty three cluster trials were included in this systematic review. Non-adherence was reported in 56 cluster trials. Among these, 19 reported a treatment efficacy estimate: per protocol in 15 and as treated in 4. No study discussed the assumptions made by these methods, their plausibility or the sensitivity of the results to deviations from these assumptions. LIMITATIONS: The year of publication of the cluster trials included in this review (2011) could be considered a limitation of this study; however, no new guidelines regarding the reporting and the handling of non-adherence for cluster trials have been published since. In addition, a single reviewer undertook the data extraction. To mitigate this, a second reviewer conducted a validation of the extraction process on 15 randomly selected reports. Agreement was satisfactory (93%). CONCLUSION: Despite the recommendations of the Consolidated Standards of Reporting Trials statement extension to cluster randomised trials, treatment adherence is under-reported. Among the trials providing adherence information, there was substantial variation in how adherence was defined, handled and reported. Researchers should discuss the assumptions required for the results to be interpreted causally and whether these are scientifically plausible in their studies. Sensitivity analyses to study the robustness of the results to departures from these assumptions should be performed.

Research Design Characteristics of Published Pharmacologic Randomized Clinical Trials for Irritable Bowel Syndrome and Chronic Pelvic Pain Conditions: An ACTTION Systematic Review.

Chronic pain conditions occurring in the lower abdomen and pelvis are common, often challenging to manage, and can negatively affect health-related quality of life. Methodological challenges in designing randomized clinical trials (RCTs) for these conditions likely contributes to the limited number of available treatments. The goal of this systematic review of RCTs of pharmacologic treatments for irritable bowel syndrome and 3 common chronic pelvic pain conditions are to: 1) summarize the primary end points and entry criteria, and 2) evaluate the clarity of reporting of important methodological details. In total, 127 RCTs were included in the analysis. The most common inclusion criteria were a minimum pain duration (81%), fulfilling an established diagnostic criteria (61%), and reporting a minimum pain intensity (42%). Primary end points were identified for only 57% of trials. These end points, summarized in this article, were highly variable. The results of this systematic review can be used to inform future research to optimize the entry criteria and outcome measures for pain conditions occurring in the lower abdomen and pelvis, to increase transparency in reporting to allow for proper interpretation of RCT results for clinical and policy applications, and to facilitate the aggregation of data in meta-analyses. PERSPECTIVE: This article summarizes entry criteria and outcome measures and the clarity of reporting of these important design features in RCTs of irritable bowel syndrome and 3 common chronic pelvic pain conditions. These results can be used to improve design of future trials of these largely unaddressed pain conditions.