Cohort Multiple Randomised Controlled Trials (cmRCT) design: efficient but biased? A simulation study to evaluate the feasibility of the Cluster cmRCT design

Abstract

BackgroundThe Cohort Multiple Randomised Controlled Trial (cmRCT) is a newly proposed pragmatic trial design; recently several cmRCT have been initiated. This study tests the unresolved question of whether differential refusal in the intervention arm leads to bias or loss of statistical power and how to deal with this.MethodsWe conduct simulations evaluating a hypothetical cluster cmRCT in patients at risk of cardiovascular disease (CVD). To deal with refusal, we compare the analysis methods intention to treat (ITT), per protocol (PP) and two instrumental variable (IV) methods: two stage predictor substitution (2SPS) and two stage residual inclusion (2SRI) with respect to their bias and power. We vary the correlation between treatment refusal probability and the probability of experiencing the outcome to create different scenarios.ResultsWe found ITT to be biased in all scenarios, PP the most biased when correlation is strong and 2SRI the least biased on average. Trials suffer a drop in power unless the refusal rate is factored into the power calculation.ConclusionsThe ITT effect in routine practice is likely to lie somewhere between the ITT and IV estimates from the trial which differ significantly depending on refusal rates. More research is needed on how refusal rates of experimental interventions correlate with refusal rates in routine practice to help answer the question of which analysis more relevant. We also recommend updating the required sample size during the trial as more information about the refusal rate is gained.

Exclusion of Older Adults from Ongoing Clinical Trials on Low Back Pain: A Review of the WHO Trial Registry Database

“…The cmRCT allows the development of multiple trials and the comparison of interventions without the need to ask for further consent from the participants randomized to the control group. However, contrary to a standard RCT, in the cmRCT participants are randomized before offering the intervention that may result in post‐randomization refusal contributing to selection bias …”

“…However, contrary to a standard RCT, in the cmRCT participants are randomized before offering the intervention that may result in post-randomization refusal contributing to selection bias. 57,59 Most of the protocols planning to include older adults were designed to investigate pharmacologic interventions. However, these studies have a wide range of age and do not state the percentage of older adults that is planned to recruit or a subgroup analysis, which would prevent them from providing an evidence-based recommendation for older patients.…”

The Trials within Cohorts design faced methodological advantages and disadvantages in the exercise oncology setting

“…During the recruitment phase, the actual acceptance rate turned out to be lower than expected, and we had to increase our sample size and extend our recruitment period [11,32]. Fortunately, UMBRELLA Fit was performed within a dynamic cohort with continuous recruitment of eligible patients.…”

Erratum to: Evaluation of biases present in the cohort multiple randomised controlled trial design: a simulation study

“…The published Reference 14 [2] is incorrect, and should have cited a different article by Pate et al [3]. …”

“…Pate et al [3] should have been included in the Reference list as 14, and the subsequent references (and citations within the article text) should have been renumbered.…”