Robert J Fox, Heinz Wiendl, Christian Wolf, Nicola De Stefano, Johann Sellner, Viktoriia Gryb, Konrad Rejdak, Plamen S Bozhinov, Daniel Vitt, Hella Kohlhof, Jason Slizgi, Matej Ondrus, Valentina Sciacca, Andreas R Muehler
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Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship.</p><p><strong>Methods: </strong>In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety.</p><p><strong>Results: </strong>Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. 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引用次数: 0
摘要
背景和目的：与安慰剂相比，维多氟米钙能抑制复发缓解型多发性硬化症（RRMS）患者的MRI疾病活动。由于30毫克和45毫克在多个终点上显示出相似的活性，该研究又招募了一个低剂量队列，以进一步研究剂量-反应关系：在一项随机、安慰剂对照的2期试验中，年龄在18-55岁之间、在过去2年内复发≥2次或在过去1年内复发≥1次、在过去6个月内脑部钆增强病变≥1次的RRMS患者被随机分配（1:1）。在组群1中，患者被随机分配（1:1:1）维多夫鲁地莫司钙（30或45毫克）或安慰剂；在组群2中，患者被随机分配（10毫克）维多夫鲁地莫司钙或安慰剂（4:1），为期24周。主要终点是第24周时合并独特活性（CUA）病变的累积数量。次要终点为临床结果和安全性：在组群 1 和组群 2 中，268 名患者被随机分配到安慰剂（81 人）、10 毫克（47 人）维多夫鲁地莫司钙、30 毫克（71 人）维多夫鲁地莫司钙或 45 毫克（69 人）维多夫鲁地莫司钙。安慰剂治疗组 24 周内的平均累积 CUA 病变为 5.8（95% CI 4.1-8.2），10 毫克治疗组为 5.9（95% CI 3.9-9.0），30 毫克治疗组为 1.4（95% CI 0.9-2.1），45 毫克治疗组为 1.7（95% CI 1.1-2.5）。血清神经丝轻链的下降呈剂量依赖性。24周后确诊残疾恶化的患者中，接受安慰剂治疗的患者有3例（3.7%），接受任何剂量维多氟米钙治疗的患者有3例（1.6%）。35例（43%）安慰剂患者发生了治疗突发不良事件，而10毫克或任何剂量维多夫鲁地莫司钙组分别为11例（23%）和71例（37%）。肝酶升高和感染的发生率在安慰剂组和任何剂量的维多夫鲁地莫司钙组之间相似。未观察到新的安全信号：讨论：与安慰剂相比，每日剂量为30毫克和45毫克的维多夫卢地莫司钙能抑制新脑损伤的发生，但不能抑制10毫克的脑损伤，因此最低有效剂量为30毫克：该研究提供了II级证据，表明在过去6个月中，在患有活动性RRMS且脑部病变≥1个Gd+的成人中，维多氟米司钙可减少活动性病变的累积数量：试验注册信息：ClinicalTrials.gov（NCT03846219）和EudraCT（2018-001896-19）。
Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial.
Background and objectives: Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship.
Methods: In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety.
Results: Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed.
Discussion: Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg.
Classification of evidence: This study provides Class II evidence that among adults with active RRMS and ≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium.
Trial registration information: ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).
期刊介绍：
Neurology Neuroimmunology & Neuroinflammation is an official journal of the American Academy of Neurology. Neurology: Neuroimmunology & Neuroinflammation will be the premier peer-reviewed journal in neuroimmunology and neuroinflammation. This journal publishes rigorously peer-reviewed open-access reports of original research and in-depth reviews of topics in neuroimmunology & neuroinflammation, affecting the full range of neurologic diseases including (but not limited to) Alzheimer's disease, Parkinson's disease, ALS, tauopathy, and stroke; multiple sclerosis and NMO; inflammatory peripheral nerve and muscle disease, Guillain-Barré and myasthenia gravis; nervous system infection; paraneoplastic syndromes, noninfectious encephalitides and other antibody-mediated disorders; and psychiatric and neurodevelopmental disorders. Clinical trials, instructive case reports, and small case series will also be featured.
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