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

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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 ( IF 48.0 ) Pub Date : 2021-08-19 , DOI: 10.1016/s1474-4422(21)00179-4
J William L Brown ₁ , Nick G Cunniffe ₂ , Ferran Prados ₃ , Baris Kanber ₄ , Joanne L Jones ₂ , Edward Needham ₂ , Zoya Georgieva ₂ , David Rog ₅ , Owen R Pearson ₆ , James Overell ₇ , David MacManus ₈ , Rebecca S Samson ₈ , Jonathan Stutters ₈ , Charles Ffrench-Constant ₉ , Claudia A M Gandini Wheeler-Kingshott ₁₀ , Carla Moran ₁₁ , Paul D Flynn ₁₂ , Andrew W Michell ₂ , Robin J M Franklin ₁₃ , Siddharthan Chandran ₁₄ , Daniel R Altmann ₁₅ , Declan T Chard ₁₆ , Peter Connick ₉ , Alasdair J Coles ₂

Affiliation

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.
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; Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, London, UK; e-Health Center, Universitat Oberta de Catalunya, Barcelona, Spain.
NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, University College London, London, UK; Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, London, UK; National Institute for Health Research Biomedical Research Centre, University College London Hospitals NHS Foundation Trust and University College London, London, UK.
Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK.
Department of Neurology, Swansea Bay University Health Board, Swansea, UK.
Product Development Neuroscience, F Hoffmann-La Roche, Basel, Switzerland; Institute of Neurological Sciences, University of Glasgow, Glasgow, UK.
NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
NMR 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 of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK.
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
Medical Statistics Department, London School of Hygiene & Tropical Medicine, London, UK.
NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, University College London, London, UK; National Institute for Health Research Biomedical Research Centre, University College London Hospitals NHS Foundation Trust and University College London, London, UK.

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.

中文翻译：

贝沙罗汀治疗复发缓解型多发性硬化症 (CCMR One) 患者的安全性和有效性：一项随机、双盲、安慰剂对照、平行组 2a 期研究

背景

多发性硬化症会出现进行性残疾，因为脱髓鞘的晚期后果是中枢神经系统轴突退化。在动物中，视黄酸受体 RXR-γ 激动剂可促进髓鞘再生。我们的目的是评估非选择性视黄醇 X 受体激动剂促进多发性硬化症患者髓鞘再生的安全性和有效性。

方法

这项随机、双盲、安慰剂对照、平行组 2a 期试验 (CCMR One) 招募了来自英国两个中心的复发缓解型多发性硬化症患者。符合资格的参与者年龄为 18-50 岁，并且已接受富马酸二甲酯治疗至少 6 个月。通过独立统计学家运行的基于网络的系统，参与者被随机分配（1:1），通过使用四个二元因素的概率加权最小化，每天接受 300 mg/m ²体表面积的口服贝沙罗汀或口服安慰剂6个月。参与者、研究人员和结果评估人员对治疗分配情况不知情。在基线和 6 个月时进行 MRI 扫描。主要安全性结果是贝沙罗汀引起的不良事件和停药的数量。主要疗效结果是基线磁化转移比小于患者内中位数的病灶在基线和第 6 个月之间平均病灶磁化转移比的患者水平变化。我们分析了安全人群的主要安全结果，其中包括接受至少一剂分配治疗的参与者。我们分析了意向治疗人群（包括完成研究的所有患者）的主要疗效结果。这项研究已在 ISRCTN 登记处注册，编号为 14265371，并已完成。

发现

2017年1月17日至2019年5月17日期间，52名参与者被随机分配接受贝沙罗汀（n=26）或安慰剂（n=26）治疗。接受贝沙罗汀治疗的参与者的不良事件平均数（6·12 [SD 3·09]；总共 159 起事件）高于接受安慰剂的参与者（1·63 [SD 1·50]；总共 39 起事件）。所有接受贝沙罗汀治疗的参与者均出现至少一种不良事件，其中包括中枢性甲状腺功能减退症（n=26对比安慰剂组无）、高甘油三酯血症（n=24对比安慰剂组无）、皮疹（n=13对比安慰剂组 1 例）和中性粒细胞减少症（n=10 vs安慰剂组无）。由于不良事件，五名（19%）服用贝沙罗汀的参与者和两名（8%）服用安慰剂的参与者停止了研究药物。安慰剂治疗的参与者中的一次胆囊炎发作是唯一的严重不良事件。贝沙罗汀组 (0·25 百分比单位 [pu; SD 0·98]) 和安慰剂组 (0·09 pu [0·84]) 之间平均病灶磁化转移率的变化没有差异；调整后的贝沙罗汀组与安慰剂组之间的差异0·16 pu，95% CI –0·39 至 0·71；p=0·55)。