美金刚和曲唑酮与安慰剂治疗运动神经元疾病(MND SMART)的安全性和疗效:第三阶段、多臂、多阶段、随机、自适应平台试验第一周期的第二阶段中期分析。

IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY
Lancet Neurology Pub Date : 2024-11-01 Epub Date: 2024-09-19 DOI:10.1016/S1474-4422(24)00326-0
Suvankar Pal, Jeremy Chataway, Robert Swingler, Malcolm R Macleod, Neil O Carragher, Giles Hardingham, Bhuvaneish Thangaraj Selvaraj, Colin Smith, Charis Wong, Judith Newton, Dawn Lyle, Amy Stenson, Rachel S Dakin, Amarachi Ihenacho, Shuna Colville, Arpan R Mehta, Nigel Stallard, James R Carpenter, Richard A Parker, Catriona Keerie, Christopher J Weir, Bruce Virgo, Stevie Morris, Nicola Waters, Beverley Gray, Donald MacDonald, Euan MacDonald, Mahesh K B Parmar, Siddharthan Chandran
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引用次数: 0

摘要

背景:运动神经元病是一组以运动神经元选择性丧失为特征的渐进性不治之症,因此迫切需要快速确定有效的疾病改变疗法。MND SMART 试验的目的是对照一个同期安慰剂对照组,高效、明确地测试有前景的干预措施的安全性和有效性。我们现在报告美金刚和曲唑酮的第二阶段中期分析结果:MND SMART是一项由研究者领导的第3阶段、双盲、安慰剂对照、多臂、多阶段、随机、适应性平台试验,在英国的20家医院中心进行招募。18岁以上确诊为肌萎缩侧索硬化症(根据修订后的埃斯科里亚尔标准分类)、原发性侧索硬化症、进行性肌萎缩或进行性球麻痹的患者,无论病程长短,均有资格参加筛选。采用计算机生成的最小化算法,通过安全的网络系统将参与者随机分配(1:1:1)为每天一次口服曲唑酮 200 毫克、每天一次口服美金刚 20 毫克或匹配的安慰剂。共同主要结局指标为临床功能(以肌萎缩侧索硬化症功能评定量表修订版(ALSFRS-R)的变化率衡量)和存活率。比较分四个阶段进行,并预先确定了在第一和第二阶段结束时停止比较的标准。我们报告的是第二阶段结果的中期分析,即每组 100 名参与者(不包括长期存活者,定义为自基线确诊后超过 8 年)完成至少 12 个月的候选研究药物随访。该试验已在欧洲临床试验注册中心(2019-000099-41)和ClinicalTrials.gov(NCT04302870)上注册,目前正在进行中:2020年2月27日至2023年7月24日(中期分析二的数据库锁定期),554名运动神经元病患被随机分配到美金刚(183人[33%])、曲唑酮(185人[33%])或安慰剂(186人[34%])中。主要中期分析人群包括530名参与者,其中175人(33%)被分配了美金刚,175人(33%)被分配了曲唑酮,180人(34%)被分配了安慰剂。在12个月的随访中,美金刚每月ALSFRS-R的平均变化率为-0-650,曲唑酮为-0-625,安慰剂为-0-655(美金刚与安慰剂的估计平均差异为0-033,单侧90% CI较低水平为-0-085;单侧P=0-36;曲唑酮与安慰剂的估计平均差异为0-065,-0-051;单侧P=0-24)。单侧P值均高于10%的显著性阈值,表明美金刚组和曲唑酮组均不符合继续治疗的标准。有 483 名参与者至少出现过一次不良事件(安慰剂组 145 人 [77%],美金刚组 170 人 [91%],曲唑酮组 168 人 [90%])。88名参与者至少出现过一次严重不良事件(美金刚37例[20%]、曲唑酮27例[14%]、安慰剂24例[13%])。共有 11 例严重不良事件导致治疗中止。美金刚组有49例死亡,曲唑酮组52例死亡,安慰剂组48例死亡:与安慰剂相比,美金刚和曲唑酮均未改善疗效。这一结果足以证明,在本研究评估的剂量下,不再对运动神经元疾病患者进行曲唑酮或美金刚试验。多臂多阶段设计在缩短时间、降低成本、减少参与人数以得出最终结果方面具有重要优势:资助机构:尤安-麦克唐纳中心、苏格兰 MND、我的名字叫多迪基金会和 Baillie Gifford。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial.

Background: Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone.

Methods: MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing.

Findings: Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0·650 for memantine, -0·625 for trazodone, and -0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level -0·085; one-sided p=0·36; trazodone vs placebo: 0·065, -0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group.

Interpretation: Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result.

Funding: The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford.

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来源期刊
Lancet Neurology
Lancet Neurology 医学-临床神经学
CiteScore
58.70
自引率
1.00%
发文量
572
审稿时长
6-12 weeks
期刊介绍: The Lancet Neurology is the world-leading clinical neurology journal. It publishes original research that advocates for change in, or sheds light on, neurological clinical practice. The topics covered include cerebrovascular disease, Alzheimer's disease and other dementias, epilepsy, migraine, neurological infections, movement disorders, multiple sclerosis, neuromuscular disorders, peripheral nerve disorders, pediatric neurology, sleep disorders, and traumatic brain injury. The journal publishes a range of article types, including Articles (including randomized clinical trials and meta-analyses), Review, Rapid Review, Comment, Correspondence, and Personal View. It also publishes Series and Commissions that aim to shape and drive positive change in clinical practice and health policy in areas of need in neurology. The Lancet Neurology is an internationally trusted source of clinical, public health, and global health knowledge. It has an Impact Factor of 48.0, making it the top-ranked clinical neurology journal out of 212 journals worldwide.
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