评估辛伐他汀在延缓继发进展型多发性硬化症残疾进展中的有效性（MS-STAT2）：英国一项多中心、随机对照、双盲、3期临床试验方案
Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK.
作者信息
Blackstone James, Williams Thomas, Nicholas Jennifer M, Bordea Ekaterina, De Angelis Floriana, Bianchi Alessia, Calvi Alberto, Doshi Anisha, John Nevin, Apap Mangion Sean, Wade Charles, Merry Rachel, Barton Gil, Lyle Dawn, Jarman Elisabeth, Mahad Don, Shehu Abdullah, Arun Tarunya, McDonnell Gavin, Geraldes Ruth, Craner Matthew, Hillier Charles, Ganesalingam Jeban, Fisniku Leonora, Hobart Jeremy, Spilker Cord, Robertson Neil, Kalra Seema, Pluchino Stefano, Harikrishnan Sreedharan, Mattoscio Miriam, Harrower Timothy, Young Carolyn, Lee Martin, Chhetri Suresh, Ahmed Fayyaz, Rog David, Silber Eli, Gallagher Paul, Duddy Martin, Straukiene Agne, Nicholas Richard, Rice Claire, Nixon Stuart J, Beveridge Judy, Hawton Annie, Tebbs Susan, Braisher Marie, Giovannoni Gavin, Ciccarelli Olga, Greenwood John, Thompson Alan J, Hunter Rachael, Pavitt Sue, Pearson Owen, Evangelou Nikos, Sharrack Basil, Galea Ian, Chandran Siddharthan, Ford Helen L, Frost Chris, Chataway Jeremy
机构信息
Comprehensive Clinical Trials Unit, University College London, London, UK.
Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK.
出版信息
BMJ Open. 2024 Sep 16;14(9):e086414. doi: 10.1136/bmjopen-2024-086414.
INTRODUCTION
There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS.
METHODS AND ANALYSIS
MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur.
ETHICS AND DISSEMINATION
The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations.
TRIAL REGISTRATION NUMBERS
NCT03387670; ISRCTN82598726.
引言
对于能够影响继发进展型多发性硬化症（SPMS）残疾进展的疾病修饰疗法，仍存在未得到满足的高度需求。在2期MS-STAT研究取得阳性结果后，MS-STAT2 3期试验将评估重新利用的高剂量辛伐他汀在减缓SPMS残疾进展方面的疗效和成本效益。
方法与分析
MS-STAT2将是一项多中心、随机、安慰剂对照、双盲试验，参与者年龄在25至65岁（含）之间，患有SPMS，扩展残疾状态量表（EDSS）评分为4.0-6.5（含）。在过去2年中，残疾增加的主要原因必须是病情稳定进展而非复发。参与者将按1:1的比例分配到辛伐他汀组或安慰剂组。活性治疗剂量为每日80毫克，在每日40毫克服用1个月后开始。英国各地的31家医院将参与。主要结局是每6个月（确认的）残疾进展情况，以相对于EDSS基线评分的变化来衡量。需要招募1050名参与者以实现总共330次进展事件，从而有90%的把握证明与安慰剂相比，残疾进展相对降低30%。随访期为36个月，对于没有确认进展的患者可延长至18个月。临床医生报告的测量指标包括25英尺定时步行试验；9孔插钉试验；单指模态试验；斯隆低对比度视力试验；复发评估；改良Rankin量表和多发性硬化症简短国际认知评估量表。患者报告的结局包括特定于MS的步行、疲劳和影响量表。将进行健康经济分析。
伦理与传播
该方案已获得伦敦-威斯敏斯特研究伦理委员会（17/LO/1509）的批准。本手稿基于2024年2月26日的方案版本8.0。试验结果将通过同行评审出版物和会议报告进行传播。
试验注册号
NCT03387670；ISRCTN82598726。
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