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

BACKGROUND: The 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: The 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.