• BrownJ William LJWLDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, UK; NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, University College London, London, UK; Clinical Outcomes R, Nick G Cunniffe, Ferran Prados, Baris Kanber, Joanne L Jones, Edward Needham, Zoya Georgieva, David Rog, Owen R Pearson, James Overell, David MacManus, Rebecca S Samson, Jonathan Stutters, Charles Ffrench-Constant, Gandini Wheeler-KingshottClaudia A MCAMNMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, University College London, London, UK; Brain Connectivity Centre, IRCCS Mondino Foundation, Pavia, Italy; Department, Carla Moran, Paul D Flynn, Andrew W Michell, FranklinRobin J MRJMDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Siddharthan Chandran, Daniel R Altmann, Declan T Chard, Peter Connick, and Alasdair J Coles.
• Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, University College London, London, UK; Clinical Outcomes Research Unit, University of Melbourne, Melbourne, VIC, Australia.
• Lancet Neurol. 2021 Sep 1; 20 (9): 709720709-720.

BackgroundProgressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis.MethodsThis randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18-50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed.FindingsBetween Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene-placebo difference 0·16 pu, 95% CI -0·39 to 0·71; p=0·55).InterpretationWe do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies.FundingMultiple Sclerosis Society of the United Kingdom.Copyright © 2021 Elsevier Ltd. All rights reserved.

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