Enhanced trial efficiency of the novel "contemporaneous control recapture" parallel-cohort RCT design: Methods and application in the CRITICAL-Kids-TP trial.

The efficiency and generalizability of the traditional randomized clinical trial (RCT) design are reduced by the exclusion of otherwise eligible participants who decline randomization or undergo early withdrawal due to missed protocol-specified windows for randomization and/or first dose of the investigational drug. These limitations are particularly challenging for RCTs targeting rare diseases. In this report, we describe a novel adaptation to the previously-described "parallel-cohort RCT design", in which these up-front losses in an RCT are recaptured into a parallel, non-randomized, contemporaneous control cohort that augments the randomized controls. We also outline various statistical approaches employed to assure congruence of this non-randomized control group to the control arm of the randomized population, prior to analysis. Lastly, we describe the application of the "contemporaneous control recapture" parallel-cohort RCT design in the CRITICAL-Kids-TP trial (www.clinicaltrials.gov; NCT06628778), a proposed phase 3 trial of pharmacological thromboprophylaxis versus usual care (no pharmacological thromboprophylaxis) in critically ill adolescents.