6E-03 - A Target Trial Emulation with an Extension to Subgroups: an Example for Relapsing-Remitting Multiple Sclerosis

Background: The target trial emulation framework (TTE) helps reducing bias in observational analyses and improves transparency of design. However, conclusions are also limited to the restricted trial populations. Therefore, knowledge gaps for neglected subpopulations, such as elderly, often remain.

Objectives: In this study, we emulated the CONFIRM trial using strict eligibility criteria, and compared the estimates to a pragmatic scenario which included otherwise ineligible subgroups.

Methods: CONFIRM studied efficacy of dimethyl fumarate (DMF) and glatiramer acetate (GA) in reducing relapses in 709 relapsing-remitting multiple sclerosis (RRMS) patients. Here, we designed a retrospective cohort study, where we 1) adhered to original trial criteria and 2) followed a pragmatic approach which included subgroups. Outcomes were the annualized relapse rate (ARR) and the probability of experiencing a relapse, adjusted for covariates and overlap weights.

Results: Using strict eligibility criteria, 288 RRMS patients met the eligibility criteria (111 DMF, 177 GA). In the pragmatic scenario, 1831 patients were included (1072 DMF, 759 GA). The ARR ratio for DMF versus GA was 0.76 (95%CI 0.53-0.99) in the CONFIRM trial, 0.75 (95%CI: 0.44-1.29) in the strict scenario, and 0.58 (95% CI: 0.36-0.94) in the pragmatic scenario. Similarly, the HR for the probability of experiencing a relapse was 0.93 (95%CI 0.72-1.20), 1.05 (95%CI: 0.83-1.33) and 0.56 (95%CI: 0.46-0.67) respectively. Post-hoc analysis implied the existence of calendar bias in estimating proportional hazards.

Conclusions: Comparable results between CONFIRM and the strict scenario were observed. In the second step, methodological advantages of TTEs were thereby extended to excluded subgroups, thus embracing the added value of observational data, that is, the wider variety in the patient population often ignored in experimental settings.