Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One):a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study

Brown, J. William L., Cunniffe, Nick G., Prados, Ferran, Kanber, Baris, Jones, Joanne L., Needham, Edward, Georgieva, Zoya, Rog, David, Pearson, Owen R., Overell, James, MacManus, David, Samson, Rebecca S., Stutters, Jonathan, ffrench-Constant, Charles ORCID: https://orcid.org/0000-0002-5621-3377, Gandini Wheeler-Kingshott, Claudia A.M., Moran, Carla, Flynn, Paul D., Michell, Andrew W., Franklin, Robin J. M., Chandran, Siddharthan, Altmann, Daniel R., Chard, Declan T., Connick, Peter and Coles, Alasdair J. (2021) Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One):a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study. The Lancet Neurology, 20 (9). pp. 709-720. ISSN 1474-4422

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Abstract

Background: Progressive 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.  Methods: This 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.  Findings: Between 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).  Interpretation: We 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.  Funding: Multiple Sclerosis Society of the United Kingdom.

Item Type: Article
Additional Information: Funding Information: This work was funded by the Multiple Sclerosis Society of the United Kingdom. We are grateful for the support and advice of Christian Pathak and Susan Scott, MS Society Research Network Members, on the trial steering committee. NGC and JWLB were supported by the Thorne Family Foundation and the Grand Charity of the Freemasons. FP, BK, and DTC are supported by the NIHR UCLH Biomedical Research Centre. The Cambridge trial team is supported by the NIHR Cambridge Biomedical Research Centre. JLJ was funded by the Wellcome Trust (RG79413). CAMGW-K receives funds from the Multiple Sclerosis Society of the United Kingdom (#77), Wings for Life (#169111), Horizon2020 (CDS-QUAMRI, #634541), and the Biomedical Research Centre (#BRC704/CAP/CGW). We are very grateful to the neurologists and multiple sclerosis nurses at the National Hospital for Neurology and Neurosurgery (London, UK) and the Norfolk and Norwich University Hospital (Norwich, UK) who referred patients to be considered for entry into the trial. Funding Information: JWLB reports personal fees from Biogen for real-world evidence consultation, outside the submitted work. NGC reports grants from the Multiple Sclerosis Society of the United Kingdom, during the conduct of the study. JLJ reports grants and personal fees from Sanofi, outside the submitted work. DR reports grants from Merck, Roche, Biogen, MedDay, Sanofi Genzyme, Novartis, TG Therapeutics, and Mitsubishi, and personal fees from Merck, Roche, Biogen, MedDay, Sanofi Genzyme, Novartis, Janssen, and Celgene, outside the submitted work. ORP reports personal fees from Biogen, Genzyme, Merck, Novartis, Celegene, and Roche, outside the submitted work. JO reports grants from Hoffmann La-Roche, Biogen, Novartis, and Sanofi Genzyme, personal fees from Hoffmann La-Roche, Biogen, Teva, Novartis, Celgene, Medday Pharmaceuticals, EMD Serono, Sanofi Genzyme, Web MD Global, and Allergan, and employment from Hoffmann La-Roche, outside the submitted work, and is a shareholder of Hoffmann La-Roche. Cf-C reports grants from Roche, outside the submitted work. CM reports personal fees from Sanofi, AstraZeneca, and Apitope, and non-financial support from Sanofi and AstraZeneca, outside the submitted work. RJMF reports grants from Biogen, and personal fees from Biogen, Frequency Therapeutics, and Rewind Therapeutics, outside the submitted work. SC reports funding from Phenotherapeutics, outside the submitted work. DTC reports grants from the Multiple Sclerosis Society of the United Kingdom during the conduct of the study, and personal fees from Biogen and Hoffmann-La Roche, grants from the International Progressive MS Alliance and the Multiple Sclerosis Society of the United Kingdom, and infrastructure support from the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, outside the submitted work. AJC reports grants from the Multiple Sclerosis Society of the United Kingdom during the conduct of the study. All other authors declare no competing interests. Funding Information: This work was funded by the Multiple Sclerosis Society of the United Kingdom. We are grateful for the support and advice of Christian Pathak and Susan Scott, MS Society Research Network Members, on the trial steering committee. NGC and JWLB were supported by the Thorne Family Foundation and the Grand Charity of the Freemasons. FP, BK, and DTC are supported by the NIHR UCLH Biomedical Research Centre. The Cambridge trial team is supported by the NIHR Cambridge Biomedical Research Centre. JLJ was funded by the Wellcome Trust (RG79413). CAMGW-K receives funds from the Multiple Sclerosis Society of the United Kingdom (#77), Wings for Life (#169111), Horizon2020 (CDS-QUAMRI, #634541), and the Biomedical Research Centre (#BRC704/CAP/CGW). We are very grateful to the neurologists and multiple sclerosis nurses at the National Hospital for Neurology and Neurosurgery (London, UK) and the Norfolk and Norwich University Hospital (Norwich, UK) who referred patients to be considered for entry into the trial.
Uncontrolled Keywords: clinical neurology ,/dk/atira/pure/subjectarea/asjc/2700/2728
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 20 Jul 2022 11:30
Last Modified: 26 Jul 2022 00:23
URI: https://ueaeprints.uea.ac.uk/id/eprint/86721
DOI: 10.1016/S1474-4422(21)00179-4

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