维达氟莫司钙在复发型多发性硬化症中的安全性和剂量反应：一项安慰剂对照2期试验的扩展结果
Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial.
作者信息
Fox Robert J, Wiendl Heinz, Wolf Christian, De Stefano Nicola, Sellner Johann, Gryb Viktoriia, Rejdak Konrad, Bozhinov Plamen S, Vitt Daniel, Kohlhof Hella, Slizgi Jason, Ondrus Matej, Sciacca Valentina, Muehler Andreas R
机构信息
From the Mellen Center for Multiple Sclerosis (R.J.F.), Cleveland Clinic, OH; Department of Neurology with Institute of Translational Neurology (H.W.), University of Münster, Germany; Lycalis sprl (C.W.), Brussels, Belgium; Department of Medicine (N.D.S.), Surgery and Neuroscience, University of Siena, Italy; Department of Neurology (J. Sellner), Landesklinikum Mistelbach-Gänserndorf, Austria; Regional Clinical Hospital Department of Vascular Neurology (V.G.), Ivano-Frankivsk, Ukraine; Department of Neurology (K.R.), Medical University of Lublin, Lublin, Poland; Medical University of Pleven (P.S.B.), Bulgaria; Immunic AG (D.V., H.K., M.O., V.S., A.R.M.), Gräfelfing, Germany; and independent consultant (J. Slizgi), Raleigh, NC.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200208. doi: 10.1212/NXI.0000000000200208. Epub 2024 Apr 25.
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).
背景与目的
在2期EMPhASIS研究的首个队列中，与安慰剂相比，维达氟莫司钙可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毫克剂量在多个终点显示出相当的活性，该研究纳入了一个额外的低剂量队列，以进一步研究剂量反应关系。
方法
在一项随机、安慰剂对照的2期试验中，纳入年龄在18至55岁之间、在过去2年中复发≥2次或在过去1年中复发≥1次且在过去6个月中有≥1个钆增强脑病变的RRMS患者。患者被随机分配（1:1:1）接受维达氟莫司钙（30或45毫克）或安慰剂治疗（队列1），以及维达氟莫司钙（10毫克）或安慰剂（4:1）治疗（队列2），为期24周。主要终点是第24周时合并的独特活动性（CUA）病变的累积数量。次要终点是临床结局和安全性。
结果
在队列1和队列2中，共有268例患者被随机分配接受安慰剂（n = 81）、10毫克维达氟莫司钙（n = 47）、30毫克维达氟莫司钙（n = 71）或45毫克维达氟莫司钙（n = 69）治疗。安慰剂组24周内CUA病变的平均累积数为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）。血清神经丝轻链呈剂量依赖性下降。24周后确认残疾恶化的患者数量，接受安慰剂治疗的有3例（3.7%），接受任何剂量维达氟莫司钙治疗的有3例（1.6%）。安慰剂组35例（43%）患者发生治疗中出现的不良事件，而10毫克维达氟莫司钙组和任何剂量维达氟莫司钙组分别有11例（23%）和71例（37%）患者发生。安慰剂组与任何剂量维达氟莫司钙组之间肝酶升高和感染的发生率相似。未观察到新的安全信号。
讨论
与安慰剂相比，维达氟莫司钙每日剂量为30毫克和45毫克时可抑制新脑病变的发生，但10毫克剂量时无此作用，确定最低有效剂量为30毫克。
证据分级
本研究提供了II级证据，表明在过去6个月中有活动性RRMS且有≥1个钆增强脑病变的成年人中，维达氟莫司钙可使活动性病变的累积数量减少。
试验注册信息
ClinicalTrials.gov（NCT03846219）和EudraCT（2018 - 001896 - 19）。
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