Introduction
Multiple sclerosis (MS) is a chronic, immune-mediated, and neurodegenerative disease of the central nervous system. The systematic review aimed to explore trends and discussion points in clinical trial design and primary endpoints (PEs) for phase II and III trials intended to modify the natural course of RMS, comparing them to regulatory guidelines and expert recommendations.
Methods
The review utilized data from ClinicalTrials.gov, the EU Clinical Trials Register, and the Japan Registry of Clinical Trials, evaluating 60 trials. The selection criteria focused on trials intended to modify the natural course of RMS, including relapsing-remitting MS (RRMS), and were scheduled to begin between 2017 and 2022.
Results
The dominant clinical trial design was a randomized controlled parallel-arms trial. In adult phase III confirmatory trials, the most common designs were active-controlled double-blind trials (53%) and active-controlled open-label assessor-masking trials (16%). For adult phase II dose-finding trials, placebo- and active-controlled double-blind trials were prevalent (44%). Pediatric phase III confirmatory trials mostly used active-controlled double-blind trials (38%) and active-controlled open-label non-masking trials (25%).
The most common primary endpoints varied by trial phase and patient group. In adult confirmatory trials, the annual relapse rate (ARR) was the most common PE (56%), followed by no evidence of disease activity-3 (NEDA-3) (13%). Adult dose-finding trials frequently used the cumulative number of T1 gadolinium-enhancing lesions (56%) and combined unique active lesions (22%) as PEs. Pediatric confirmatory trials often used ARR (38%) and time to first relapse (25%) as PEs.
Discussion
The review suggests that some parts of the regulatory guidelines and expert recommendations need revision to better reflect current clinical trial practices. The findings highlight the importance of considering more potent disease-modifying therapies (DMTs) and the necessity for PEs closer to complete remission, such as NEDA-3. The study also notes the potential of incorporating historical data in pediatric non-inferiority trials as a mainstream option for confirmatory trials.
Conclusion
This systematic review provides valuable insights into the current trends and challenges in RMS clinical trial design and primary endpoints. It underscores the need for ongoing dialogue between researchers, regulatory agencies, and experts to refine guidelines and recommendations, ensuring they remain relevant and supportive of innovative and effective clinical trial designs.
