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BackgroundSubstantial amounts of public funds are invested in health research worldwide. Publicly funded randomised controlled trials (RCTs) often recruit participants at a slower than anticipated rate. Many trials fail to reach their planned sample size within the envisaged trial timescale and trial funding envelope.ObjectivesTo review the consent, recruitment and retention rates for single and multicentre randomised control trials funded and published by the UK's National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme.Data sources and study selectionHTA reports of individually randomised single or multicentre RCTs published from the start of 2004 to the end of April 2016 were reviewed.Data extractionInformation was extracted, relating to the trial characteristics, sample size, recruitment and retention by two independent reviewers.Main outcome measuresTarget sample size and whether it was achieved; recruitment rates (number of participants recruited per centre per month) and retention rates (randomised participants retained and assessed with valid primary outcome data).ResultsThis review identified 151 individually RCTs from 787 NIHR HTA reports. The final recruitment target sample size was achieved in 56% (85/151) of the RCTs and more than 80% of the final target sample size was achieved for 79% of the RCTs (119/151). The median recruitment rate (participants per centre per month) was found to be 0.92 (IQR 0.43–2.79) and the median retention rate (proportion of participants with valid primary outcome data at follow-up) was estimated at 89% (IQR 79–97%).ConclusionsThere is considerable variation in the consent, recruitment and retention rates in publicly funded RCTs. Investigators should bear this in mind at the planning stage of their study and not be overly optimistic about their recruitment projections.

Registry-based randomized controlled trials are defined as pragmatic trials that use registries as a platform for case records, data collection, randomization, and follow-up. Recently, the application of registry-based randomized controlled trials has attracted increasing attention in health research to address comparative effectiveness research questions in real-world settings, mainly due to their low cost, enhanced generalizability of findings, rapid consecutive enrollment, and the potential completeness of follow-up for the reference population, when compared with conventional randomized effectiveness trials. However several challenges of registry-based randomized controlled trials have to be taken into consideration, including registry data quality, ethical issues, and methodological challenges. In this article, we summarize the advantages, challenges, and areas for future research related to registry-based randomized controlled trials.

We consider methods for causal inference in randomized trials nested within cohorts of trial-eligible individuals, including those who are not randomized. We show how baseline covariate data from the entire cohort, and treatment and outcome data only from randomized individuals, can be used to identify potential (counterfactual) outcome means and average treatment effects in the target population of all eligible individuals. We review identifiability conditions, propose estimators, and assess the estimators' finite-sample performance in simulation studies. As an illustration, we apply the estimators in a trial nested within a cohort of trial-eligible individuals to compare coronary artery bypass grafting surgery plus medical therapy vs. medical therapy alone for chronic coronary artery disease.

AbstractObjectivesTo evaluate the compliance with prospective registration and inclusion of the trial registration number (TRN) in published randomised controlled trials (RCTs), and to analyse the rationale behind, and detect selective registration bias in, retrospective trial registration.DesignCross sectional analysis.Data sourcesPubMed, the 17 World Health Organization’s trial registries, University of Toronto library, International Committee of Medical Journal Editors (ICMJE) list of member journals, and the InCites Journal Citation Reports.Study selection criteriaRCTs registered in any WHO trial registry and published in any PubMed indexed journal in 2018.ResultsThis study included 10 500 manuscripts published in 2105 journals. Overall, 71.2% (7473/10500) reported the TRN and 41.7% (3013/7218) complied with prospective trial registration. The univariable and multivariable analyses reported significant relations (P<0.05) between reporting the TRN and the impact factor and ICMJE membership of the publishing journal. A significant relation (P<0.05) was also observed between prospective trial registration and the registry, region, condition, funding, trial size, interval between paper registration and submission dates, impact factor, and ICMJE membership of the publishing journal. A manuscript published in an ICMJE member journal was 5.8 times more likely to include the TRN (odds ratio 5.8, 95% confidence interval 4.0 to 8.2), and a published trial was 1.8 times more likely to be registered prospectively (1.8, 1.5 to 2.2) when published in an ICMJE member journal compared with other journals. This study detected a new form of bias, selective registration bias, with a higher proportion (85.2% (616/723)) of trials registered retrospectively within a year of submission for publication. Higher rates of retrospective registrations were observed within the first three to eight weeks after enrolment of study participants. Within the 286 RCTs registered retrospectively and published in an ICMJE member journal, only 2.8% (8/286) of the authors included a statement justifying the delayed registration. Reasons included lack of awareness, error of omission, and the registration process taking longer than anticipated.ConclusionsThis study found a high compliance in reporting of the TRN for trial papers published in ICMJE member journals, but prospective trial registration was low.

Abstract Objective An important clinical question is how many patients with acute schizophrenia do not respond to antipsychotics despite being treated for adequate time and with an effective dose. However, up to date, the exact extent of the phenomenon remains unclear. Methods We calculated the nonresponse and nonremission percentages using individual patient data from 16 randomized controlled trials (RCTs). Six thousand two hundred twenty-one patients were assigned to one antipsychotic (amisulpride, flupenthixol, haloperidol, olanzapine, quetiapine, risperidone, or ziprasidone) at an adequate dose; the response was assessed at 4–6 weeks. As various definitions of nonresponse have been used in the literature, we applied 4 different cut-offs covering the whole range of percent Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) reduction (≤0%, <25%, <50%, <75%).For symptomatic remission, we used the definition proposed by Andreasen without employing the time criterion. Results The overall nonresponse for the cut-off of ≤0% PANSS/BPRS reduction was 19.8% (18.8%–20.8%); for the cut-off of <25% reduction it was 43% (41.7%–44.3%); for the cut-off of <50% reduction it was 66.5% (65.3%–67.8%); and for the cut-off of <75% reduction it was 87% (86%–87.9%). The overall percentage of no symptomatic remission was 66.9% (65.7%–68.1%). Earlier onset of illness, lower baseline severity and the antipsychotic used were significantly associated with higher nonresponse percentages. Conclusions Nonresponse and nonremission percentages were notably high. Nevertheless, the patients in our analysis could represent a negative selection since they came from short-term RCTs and could have been treated before study inclusion; thus, further response may not have been observed. Observational studies on this important question are needed.

A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes. Using individual patient data, we analysed the modifying effects of bodyweight (10 kg bands) and height (10 cm bands) on the effects of low doses (≤100 mg) and higher doses (300–325 mg or ≥500 mg) of aspirin in randomised trials of aspirin in primary prevention of cardiovascular events. We stratified the findings by age, sex, and vascular risk factors, and validated them in trials of aspirin in secondary prevention of stroke. Additionally, we assessed whether any weight or height dependence was evident for the effect of aspirin on 20-year risk of colorectal cancer or any in-trial cancer. Among ten eligible trials of aspirin in primary prevention (including 117 279 participants), bodyweight varied four-fold and trial median weight ranged from 60·0 kg to 81·2 kg (p<0·0001). The ability of 75–100 mg aspirin to reduce cardiovascular events decreased with increasing weight (pinteraction=0·0072), with benefit seen in people weighing 50–69 kg (hazard ratio [HR] 0·75 [95% CI 0·65–0·85]) but not in those weighing 70 kg or more (0·95 [0·86–1·04]; 1·09 [0·93–1·29] for vascular death). Furthermore, the case fatality of a first cardiovascular event was increased by low-dose aspirin in people weighing 70 kg or more (odds ratio 1·33 [95% CI 1·08–1·64], p=0·0082). Higher doses of aspirin (≥325 mg) had the opposite interaction with bodyweight (difference pinteraction=0·0013), reducing cardiovascular events only at higher weight (pinteraction=0·017). Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height (pinteraction=0·0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (pinteraction=0·038). Stratification by body size also revealed harms due to excess dosing: risk of sudden death was increased by aspirin in people at low weight for dose (pinteraction=0·0018) and risk of all-cause death was increased in people weighing less than 50 kg who were receiving 75–100 mg aspirin (HR 1·52 [95% CI 1·04–2·21], p=0·031). In participants aged 70 years or older, the 3-year risk of cancer was also increased by aspirin (1·20 [1·03–1·47], p=0·02), particularly in those weighing less than 70 kg (1·31 [1·07–1·61], p=0·009) and consequently in women (1·44 [1·11–1·87], p=0·0069). Low doses of aspirin (75–100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin's effects on other outcomes, including cancer, also showed interactions with body size, a one-dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required. Wellcome Trust and National Institute for Health Research Oxford Biomedical Research Centre.

Randomized noncomparative trials (RNCTs) promise reduced accrual requirements vs randomized controlled comparative trials because RNCTs do not enroll a control group and instead compare outcomes to historical controls or prespecified estimates. We hypothesized that RNCTs often suffer from two methodological concerns: (1) lack of interpretability due to group-specific inferences in nonrandomly selected samples and (2) misinterpretation due to unlicensed between-group comparisons lacking prespecification. The purpose of this study was to characterize RNCTs and the incidence of these two methodological concerns. We queried PubMed and Web of Science on September 14, 2023, to conduct a meta-epidemiological analysis of published RNCTs in any field of medicine. Trial characteristics and the incidence of methodological concerns were manually recorded. We identified 70 RNCTs published from 2002 to 2023. RNCTs have been increasingly published over time (slope = 0.28, 95% CI 0.17–0.39, P < .001). Sixty trials (60/70, 86%) had a lack of interpretability for the primary endpoint due to group-specific inferences. Unlicensed between-group comparisons were present in 36 trials (36/70, 51%), including in the primary conclusion of 31 trials (31/70, 44%), and were accompanied by significance testing in 20 trials (20/70, 29%). Only five (5/70, 7%) trials were found to have neither of these flaws. Although RNCTs are increasingly published over time, the primary analysis of nearly all published RNCTs in the medical literature was unsupported by their fundamental underlying methodological assumptions. RNCTs promise group-specific inference, which they are unable to deliver, and undermine the primary advantage of randomization, which is comparative inference. The ongoing use of the RNCT design in lieu of a traditional randomized controlled comparative trial should therefore be reconsidered.

Background Randomised controlled trials (RCTs) are the gold standard assessment for health technologies. A key aspect of the design of any clinical trial is the target sample size. However, many publicly-funded trials fail to reach their target sample size. This study seeks to assess the current state of recruitment success and grant extensions in trials funded by the Health Technology Assessment (HTA) program and the UK Medical Research Council (MRC). Methods Data were gathered from two sources: the National Institute for Health Research (NIHR) HTA Journal Archive and the MRC subset of the International Standard Randomised Controlled Trial Number (ISRCTN) register. A total of 440 trials recruiting between 2002 and 2008 were assessed for eligibility, of which 73 met the inclusion criteria. Where data were unavailable from the reports, members of the trial team were contacted to ensure completeness. Results Over half (55%) of trials recruited their originally specified target sample size, with over three-quarters (78%) recruiting 80% of their target. There was no evidence of this improving over the time of the assessment. Nearly half (45%) of trials received an extension of some kind. Those that did were no more likely to successfully recruit. Trials with 80% power were less likely to successfully recruit compared to studies with 90% power. Conclusions While recruitment appears to have improved since 1994 to 2002, publicly-funded trials in the UK still struggle to recruit to their target sample size, and both time and financial extensions are often requested. Strategies to cope with such problems should be more widely applied. It is recommended that where possible studies are planned with 90% power.

Background In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone. Methods All patients, including retrospective training ( n  = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n  = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts. Results Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25–0.74, p  = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups ( p  = 0.063), with a significant treatment interaction ( p interaction  <  0.001). This trend was also found in the validation cohort with high ( n  = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06–0.51, p  <  0.001) and low ICTOS ( n  = 175, p  = 0.31), with a significant treatment interaction ( p interaction  = 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors. Conclusion An imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment. Trial registration ClinicalTrials.gov , NCT01245959 . Registered 23 November 2010.

Cluster randomized trials (CRTs) are frequently used to evaluate interventions in low- and middle-income countries (LMICs). Robust execution and transparent reporting of randomization procedures are essential for successful implementation and accurate interpretation of CRTs. Our objectives were to review the quality of reporting and implementation of randomization procedures in a sample of parallel-arm CRTs conducted in LMICs. We selected a random sample of 300 primary reports of parallel-arm CRTs from a database of 800 CRTs conducted in LMICs between 2017 and 2022. Data were extracted by two reviewers per trial and summarized using descriptive statistics. Among 300 trials, 192 (64%) reported the method of sequence generation, 213 (71%) reported the type of randomization procedure used, 146 (49%) reported who generated the sequence, 136 (45%) reported whether randomization was implemented by an independent person, and 75 (25%) reported a method of allocation concealment. Among those reporting the methods used, suboptimal randomization procedures were common: 28% did not use a computer, 21% did not use restricted randomization, 58% did not use a statistician to generate the sequence, in 53% the person was not independent from the trial, and 80% did not use central randomization. Public randomization ceremonies were used in 10% of trials as an alternative method of allocation concealment and to reassure participants of fair allocation procedures. The conduct and reporting of randomization procedures of CRTs in LMICs is suboptimal. Dissemination of guidance to promote robust implementation of randomization in LMICs is required, and future research on the implementation of public randomization ceremonies is warranted. Cluster randomized trials (CRTs) are trials where entire groups, rather than individuals, are randomly assigned to different treatments (eg, intervention or usual care). This randomization process can be challenging in CRTs; clear reporting and proper execution are important to ensure fairness and accurate results. In this study, we reviewed how well randomization procedures were reported and carried out in 300 CRTs, selected from a larger database of 800 CRTs, conducted in low- and middle-income countries (LMICs), and published between 2017 and 2022. We found that reporting on key aspects of randomization was often incomplete: 64% reported how they created the random allocation sequence, 71% reported the type of randomization method used, 49% reported who generated the sequence, 45% reported whether a person independent from the trial handled the randomization, and 25% reported how they kept group assignments hidden until the intervention was ready to begin. Even when trials did reported these methods, many did not follow best practices: 28% did not use a computer, 21% did not apply techniques to ensure balanced treatment arms, 58% did not involve a statistician to generate the sequence, 53% had someone involved in the trial handle randomization (as opposed to an independent person), and 80% did not use central randomization to assign groups, where a third party reveals treatment assignment to groups. Interestingly, 10% of trials used public randomization ceremonies (events where group assignments are revealed in a public setting) to keep group assignments hidden until revealment and to reassure participants that the process was fair. Overall, we found that randomization procedures in CRTs were often not well reported or carried out optimally. It is important for researchers to follow established guidelines to ensure randomization is done properly in CRTs in LMICs. More research is also needed to understand how public randomization ceremonies are used in practice. [Display omitted] •Robust randomization methods are essential for cluster randomized trials (CRTs).•Improved adherence to reporting and best practices for randomization in CRTs is needed.•Public randomization ceremonies may help with implementation challenges.•Further research on the conduct of public randomization ceremonies is warranted.