The Cambridge Centre for Myelin Repair trial Two (CCMR Two): a trial protocol for a phase 2a, randomised, double-blind, placebo-controlled clinical trial of the ability of the combination of metformin and clemastine to promote remyelination in people with relapsing-remitting multiple sclerosis already on disease-modifying therapy

Abstract Background In multiple sclerosis (MS), progressive disability occurs following degeneration of demyelinated axons. A tractable approach to delay, prevent or reverse disability progression is through enhancement of endogenous remyelination. Clinical trials have deployed drugs, such as clemastine, to target the rate-limiting step in this process: differentiation of oligodendrocyte progenitor cells (OPCs). Preclinical research has shown that metformin can reverse an age-associated deficit in the responsiveness of OPCs to pro-differentiation factors. The purpose of the Cambridge Centre for Myelin Repair trial Two (CCMR Two) is to evaluate the efficacy of the combination of metformin and clemastine to promote remyelination in people with MS. Methods Participants with relapsing-remitting MS (RRMS) will be randomised 1:1 to the combination of metformin and clemastine or matched placebos and followed for 24 weeks of treatment. All participants must be stable on a disease-modifying therapy and have evidence of chronic stable optic neuropathy in at least one eye (defined by P100 latency of the visual evoked potential (VEP) ≥ 118 ms, and the absence of a history of acute optic neuritis in the preceding 2 years). The primary outcome measure will be the change in the P100 latency of the full-field VEP between baseline and week 26. It is planned to recruit a total of 70 participants. This will have 80% power to detect a reduction of 3 ms in VEP P100 latency between the two treatment groups. Secondary outcome measures will examine the change in multifocal VEP and the change in lesional magnetisation transfer ratio (MTR) for lesions stratified by location and tissue-specific cohort baseline lesional MTR values. Discussion We set out the trial design, the rationale for participant and outcome measure selection, and the pre-specified analyses. With this trial, we expect to be able to detect the structural and functional consequences of remyelination within a sample size feasible for our single-centre trial. Trial registration ClinicalTrials.gov NCT05131828, prior to participant enrolment.