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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 It is increasingly accepted that insufficient attention has been given to the patient health outcomes that are important to measure in comparative effectiveness research that will inform decision-making. The relationship between outcomes chosen for comparative effectiveness research, outcomes used in decision-making in routine care, and outcome data recorded in electronic health records (EHR) is also poorly understood. The COMET Initiative ( http://www.comet-initiative.org/ . Accessed 3 Apr 2020) supports and encourages the development and use of ‘core outcome sets’ (COS), which represent the minimum set of patient health outcomes that should be measured and reported for a specific condition. There is growing interest in identifying how COS might fit into the different stages of the healthcare research and delivery ecosystem, and whether inclusion in the EHR might facilitate this. Methods We sought to determine the degree of overlap between outcomes within COS for research and routine care, EMA, FDA and NICE guidelines, NICE quality statements/indicators, EHR and a point-of-care randomised clinical trial, using type 2 diabetes (T2D) as a case study. Results There is substantial agreement about important patient outcomes for T2D for research and healthcare, with associated coverage within the UK general practice EHR. Conclusions This case study has demonstrated the potential for efficient research and value-based healthcare when the EHR can include COS for both research and care, where the COS comprises outcomes of importance to all relevant stakeholders. However, this concordance may not hold more generally, as the focus on patient-centred outcomes may well be greater in T2D than in other conditions. Work is ongoing to examine other clinical areas, in order to highlight any current inefficiencies when health outcomes in research and healthcare do not agree with core outcomes identified by patients, clinicians and other key stakeholders.

Since some patients with psoriatic arthritis do not respond to typical drug treatments, alternatives are needed. Findings suggest that interleukins 12 and 23 might affect clinical symptoms and pathological joint changes of psoriatic arthritis. Ustekinumab is a human monoclonal antibody that inhibits receptor-binding of these cytokines. We aimed to assess the efficacy and safety of ustekinumab for psoriatic arthritis in this phase II study. We undertook a double-blind, randomised, placebo-controlled, crossover study at 24 sites in North America and Europe. Patients with active psoriatic arthritis were randomly allocated via interactive voice response system to either ustekinumab (90 mg or 63 mg) every week for 4 weeks (weeks 0–3) followed by placebo at weeks 12 and 16 (n=76; Group 1) or placebo (weeks 0–3) and ustekinumab (63 mg) at weeks 12 and 16 (n=70; Group 2). The first 12 weeks of the study were placebo-controlled. Masking was maintained to week 16 infusion, and patients were followed up to week 36. The primary endpoint was ACR20 response at week 12. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00267956. At week 12, 32 (42%) patients in Group 1 and ten (14%) in Group 2 achieved the primary endpoint (difference 28% [95% CI 14·0–41·6]; p=0·0002). Of 124 (85%) participants with psoriasis affecting 3% or more body surface area, 33 of 63 (52%) in Group 1 and three of 55 (5%) in Group 2 had a 75% or greater improvement in psoriasis area and severity index score at week 12 (47% [33·2–60·6]; p<0·0001). During the placebo-controlled period (weeks 0–12), adverse events arose in 46 (61%) patients in Group 1 and 44 (63%) in Group 2; serious adverse events were recorded in three (4%) Group 2 patients (none in Group 1). Ustekinumab significantly reduced signs and symptoms of psoriatic arthritis and diminished skin lesions compared with placebo, and the drug was well tolerated. Larger and longer term studies are needed to further characterise ustekinumab efficacy and safety for treatment of psoriatic arthritis. Centocor.

Central reading, that is, independent, off-site, blinded review or reading of imaging endpoints, has been identified as a crucial component in the conduct and analysis of inflammatory bowel disease clinical trials. Central reading is the final step in a workflow that has many parts, all of which can be improved. Furthermore, the best reading algorithm and the most intensive central reader training cannot make up for deficiencies in the acquisition stage (clinical trial endoscopy) or improve on the limitations of the underlying score (outcome instrument). In this review, academic and industry experts review scoring systems, and propose a theoretical framework for central reading that predicts when improvements in statistical power, affecting trial size and chances of success, can be expected: Multireader models can be conceptualised as statistical or non-statistical (social). Important organisational and operational factors, such as training and retraining of readers, optimal bowel preparation for colonoscopy, video quality, optimal or at least acceptable read duration times and other quality control matters, are addressed as well. The theory and practice of central reading and the conduct of endoscopy in clinical trials are interdisciplinary topics that should be of interest to many, regulators, clinical trial experts, gastroenterology societies and those in the academic community who endeavour to develop new scoring systems using traditional and machine learning approaches.

Up to 50% of patients with acute stroke are taking antihypertensive drugs on hospital admission. However, whether such treatment should be continued during the immediate post-stroke period is unclear. We therefore aimed to assess the efficacy and safety of continuing or stopping pre-existing antihypertensive drugs in patients who had recently had a stroke. The Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS) was a UK multicentre, prospective, randomised, open, blinded-endpoint trial. Patients were recruited at 49 UK National Institute for Health Research Stroke Research Network centres from January 1, 2003, to March 31, 2009. Patients aged over 18 years who were taking antihypertensive drugs were enrolled within 48 h of stroke and the last dose of antihypertensive drug. Patients were randomly assigned (1:1) by secure internet central randomisation to either continue or stop pre-existing antihypertensive drugs for 2 weeks. Patients and clinicians who randomly assigned patients were unmasked to group allocation. Clinicians who assessed 2-week outcomes and 6-month outcomes were masked to group allocation. The primary endpoint was death or dependency at 2 weeks, with dependency defined as a modified Rankin scale score greater than 3 points. Analysis was by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Register, number ISRCTN89712435. 763 patients were assigned to continue (n=379) or stop (n=384) pre-existing antihypertensive drugs. 72 of 379 patients in the continue group and 82 of 384 patients in the stop group reached the primary endpoint (relative risk 0·86, 95% CI 0·65–1·14; p=0·3). The difference in systolic blood pressure at 2 weeks between the continue group and the stop group was 13 mm Hg (95% CI 10–17) and the difference in diastolic blood pressure was 8 mm Hg (6–10; difference between groups p<0·0001). No substantial differences were observed between groups in rates of serious adverse events, 6-month mortality, or major cardiovascular events. Continuation of antihypertensive drugs did not reduce 2-week death or dependency, cardiovascular event rate, or mortality at 6 months. Lower blood pressure levels in those who continued antihypertensive treatment after acute mild stroke were not associated with an increase in adverse events. These neutral results might be because COSSACS was underpowered owing to early termination of the trial, and support the continuation of ongoing research trials. The Health Foundation and The Stroke Association.

Cancer treatment should allow patients to live better or longer lives, and ideally, both. Trial endpoints should show clinically meaningful improvements in patient survival or quality of life. Alternative endpoints such as progression-free survival, disease-free survival, and objective response rate have been used to identify benefit earlier, but their true validity as surrogate endpoints is controversial. In this Review we discuss the measurement, assessment, and benefits and limitations of trial endpoints in use for cancer treatment. Many stakeholders are affected, including regulatory agencies, industry partners, clinicians, and most importantly, patients. In an accompanying Review, reflections from individual stakeholders are incorporated into a discussion of what the future holds for clinical trial endpoints and design.

Routinely collected data (RCD) from healthcare claims and encounters are increasingly used for outcomes in randomized trials; however, methods for estimating the validity and relative precision of RCD-derived outcomes compared to those from conventional outcome ascertainment are limited. We developed an approach to measuring validity and relative precision of RCD and quantifying uncertainty. We reanalyzed data from the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) cluster-randomized, controlled trial. Eighty-six primary care practices in 10 US healthcare systems were randomized to either a multifactorial intervention delivered by nurse falls care managers, or enhanced usual care, with 5451 persons age ≥ 70 at increased fall injury risk enrolled in the study. We estimated the hazard ratio (HR) and confidence interval (CI) for STRIDE's primary outcome (time to first serious fall injury) using original study data and RCD. The ratio of the RCD HR to original HR (“ratio of HRs”) measured validity. The confidence limit ratio (CLR; upper divided by lower confidence limits of CI) measured precision, with the ratio of the CLR with RCD to the CLR from the original study data (“ratio of CLRs”), measuring relative precision. We estimated uncertainty around the ratio of HRs and ratio of CLRs using bootstrapped 95% CIs and performed sensitivity analyses to assess the effects of adaptations needed to use RCD. Among the original sample of 5451 study participants, 5036 (92%) were linked to RCD. The intervention to control HR was 0.91 (95% CI: 0.78–1.07) in RCD, compared to 0.92 (95% CI: 0.80–1.06) in the original data. Using all RCD through STRIDE's administrative end date, the ratio of HRs was 1.00 (95% CI: 0.89–1.11) and ratio of CLRs was 1.03 (95% CI: 0.96–1.06). The CI around ratio of HRs was about three-fold wider for RCD than for the original STRIDE data in individuals who linked to RCD. Relative precision of RCD improved with increased length of follow-up. Relying solely on RCD to ascertain the primary outcome in STRIDE would have resulted in similar point estimates and confidence limits for the treatment effect as in the original data. However, there was meaningful uncertainty around the estimate of validity. Efforts to validate RCD-derived outcomes for use as clinical trial endpoints should include measurement of uncertainty around validity estimates. •Routinely collected data (RCD) accurately reproduced the primary outcome of a trial.•RCD generated valid results, but with greater uncertainty.•Trials using RCD should account for uncertainty in validity.

CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn's disease. Crohn's Disease Activity Index (CDAI) scores were 250-450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn's medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥ 70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn's disease. ClinicalTrials.gov NCT00306215.

In randomized controlled trials, two endpoints may be necessary to capture the multidimensional concept of the intervention and the objectives of the study adequately. We show how to calculate sample size when defining success of a trial by combinations of superiority and/or non-inferiority aims for the endpoints. The randomized controlled trial design of the Social Fitness study uses two primary endpoints, which can be combined into five different scenarios for defining success of the trial. We show how to calculate power and sample size for each scenario and compare these for different settings of power of each endpoint and correlation between them. Compared to a single primary endpoint, using two primary endpoints often gives more power when success is defined as: improvement in one of the two endpoints and no deterioration in the other. This also gives better power than when success is defined as: improvement in one prespecified endpoint and no deterioration in the remaining endpoint. When two primary endpoints are equally important, but a positive effect in both simultaneously is not per se required, the objective of having one superior and the other (at least) non-inferior could make sense and reduce sample size.

Background Clinical trials are an essential part of evidence-based medicine. Hence, to ensure transparency and accountability in these clinical trials, policies for registration have been framed with emphasis on mandatory submission of trial elements, specifically outcome measures. As these efforts evolve further, we sought to evaluate the current status of endpoint reporting in clinical trial registries. Methods We reviewed 71 oncology related randomized controlled trials published in three high impact journals. We compared primary (PEP) and non-primary endpoints (NPEP) between the clinical trial protocols of these trials and their corresponding registration in one of the 14 primary global clinical trial registries. A discrepancy was defined as the non-reporting or absence of an endpoint in either the protocol or registry. The primary endpoint was the rate of discrepancy between secondary endpoints in clinical trial protocols and clinical trial registries. Results Of the 71 clinical trials, a discrepancy in PEP was found in only 4 trials (6%). Secondary endpoint (SEP) differences were found in 45 (63%) trials. Among these 45 trials, 36 (80%) had SEPs that were planned in the protocol but not reported in the registry and 19 (42%) had SEPs with endpoints in the registry that were not found in the protocol. The total number of SEPs that were absent from the corresponding registry and protocol were 84 and 29, respectively. Of these endpoints, 48 (57%) and 9 (31%) were included in the published report of these trials. Conclusion Although recent regulations and enhanced procedures have improved the number and quality of clinical trial registrations, inconsistencies regarding endpoint reporting still exist. Though further guidelines for the registration of clinical trials will help, greater efforts to provide a correct, easily accessible, and complete representation of planned endpoints are needed.