The greatest unmet need in multiple sclerosis (MS) are treatments that delay, prevent or reverse progression. One of the most tractable strategies to achieve this is to therapeutically enhance endogenous remyelination; doing so restores nerve conduction and prevents neurodegeneration. The biology of remyelination—centred on the activation, migration, proliferation and differentiation of oligodendrocyte progenitors—has been increasingly clearly defined and druggable targets have now been identified in preclinical work leading to early phase clinical trials. With some phase 2 studies reporting efficacy, the prospect of licensed remyelinating treatments in MS looks increasingly likely. However, there remain many unanswered questions and recent research has revealed a further dimension of complexity to this process that has refined our view of the barriers to remyelination in humans. In this review, we describe the process of remyelination, why this fails in MS, and the latest research that has given new insights into this process. We also discuss the translation of this research into clinical trials, highlighting the treatments that have been tested to date, and the different methods of detecting remyelination in people.

Objective To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS). Methods We long-listed licensed drugs with evidence of human safety, blood–brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review. Results From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine. Conclusions We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.

Objective: In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response – measured by change in magnetisation transfer ratio – is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values).Methods: We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level.Results: At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel‐level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores.Interpretation: Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post‐processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes.

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.

Objectives To analyse enrolment to interventional trials during the first wave of the COVID-19 pandemic in England and describe the barriers to successful recruitment in the circumstance of a further wave or future pandemics. Design We analysed registered interventional COVID-19 trial data and concurrently did a prospective observational study of hospitalised patients with COVID-19 who were being assessed for eligibility to one of the RECOVERY, C19-ACS or SIMPLE trials. Setting Interventional COVID-19 trial data were analysed from the clinicaltrials.gov and International Standard Randomized Controlled Trial Number databases on 12 July 2020. The patient cohort was taken from five centres in a respiratory National Institute for Health Research network. Population and modelling data were taken from published reports from the UK government and Medical Research Council Biostatistics Unit. Participants 2082 consecutive admitted patients with laboratory-confirmed SARS-CoV-2 infection from 27 March 2020 were included. Main outcome measures Proportions enrolled, and reasons for exclusion from the aforementioned trials. Comparisons of trial recruitment targets with estimated feasible recruitment numbers. Results Analysis of trial registration data for COVID-19 treatment studies enrolling in England showed that by 12 July 2020, 29 142 participants were needed. In the observational study, 430 (20.7%) proceeded to randomisation. 82 (3.9%) declined participation, 699 (33.6%) were excluded on clinical grounds, 363 (17.4%) were medically fit for discharge and 153 (7.3%) were receiving palliative care. With 111 037 people hospitalised with COVID-19 in England by 12 July 2020, we determine that 22 985 people were potentially suitable for trial enrolment. We estimate a UK hospitalisation rate of 2.38%, and that another 1.25 million infections would be required to meet recruitment targets of ongoing trials. Conclusions Feasible recruitment rates, study design and proliferation of trials can limit the number, and size, that will successfully complete recruitment. We consider that fewer, more appropriately designed trials, prioritising cooperation between centres would maximise productivity in a further wave.