A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS,Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration ( IF 2.5 ) Pub Date : 2020-09-24 , DOI: 10.1080/21678421.2020.1822410
Jeremy M Shefner ₁ , Jinsy A Andrews ₂ , Angela Genge ₃ , Carlayne Jackson ₄ , Noah Lechtzin ₅ , Timothy M Miller ₆ , Bettina M Cockroft ₇ , Lisa Meng ₇ , Jenny Wei ₇ , Andrew A Wolff ₇ , Fady I Malik ₇ , Cynthia Bodkin ₈ , Benjamin R Brooks ₉ , James Caress ₁₀ , Annie Dionne ₁₁ , Dominic Fee ₁₂ , Stephen A Goutman ₁₃ , Namita A Goyal ₁₄ , Orla Hardiman ₁₅ , Ghazala Hayat ₁₆ , Terry Heiman-Patterson ₁₇ , Daragh Heitzman ₁₈ , Robert D Henderson ₁₉ , Wendy Johnston ₂₀ , Chafic Karam ₂₁ , Matthew C Kiernan ₂₂ , Stephen J Kolb ₂₃ , Lawrence Korngut ₂₄ , Shafeeq Ladha ₂₅ , Genevieve Matte ₂₆ , Jesus S Mora ₂₇ , Merrilee Needham ₂₈ , Bjorn Oskarsson ₂₉ , Gary L Pattee ₃₀ , Erik P Pioro ₃₁ , Michael Pulley ₃₂ , Dianna Quan ₃₃ , Kourosh Rezania ₃₄ , Kerri L Schellenberg ₃₅ , David Schultz ₃₆ , Christen Shoesmith ₃₇ , Zachary Simmons ₃₈ , Jeffrey Statland ₃₉ , Shumaila Sultan ₄₀ , Andrea Swenson ₄₁ , Leonard H Van Den Berg ₄₂ , Tuan Vu ₄₃ , Steve Vucic ₄₄ , Michael Weiss ₄₅ , Ashley Whyte-Rayson ₄₆ , James Wymer ₄₇ , Lorne Zinman ₄₈ , Stacy A Rudnicki ₇

Affiliation

Barrow Neurological Institute, Phoenix, AZ, USA.
The Eleanor and Lou Gehrig ALS Center, The Neurological Institute, New York, NY, USA.
Montreal Neurological Institute, Montreal, QC, Canada.
University of Texas Health Science Center, San Antonio, TX, USA.
Johns Hopkins School of Medicine, Baltimore, MD, USA.
Washington University School of Medicine, St. Louis, MO, USA.
Cytokinetics, Inc, South San Francisco, CA, USA.
Indiana University School of Medicine, Indianapolis, IN, USA.
Atrium Health Neurosciences Institute-Carolinas Neuromuscular/ALS MDA Care Center, Charlotte, NC, USA.
Wake Forest Health Sciences, Winston-Salem, NC, USA.
CHU de Québec, Université Laval, Quebec, Canada.
Medical College of Wisconsin, Milwaukee, WI, USA.
University of Michigan, Ann Arbor, MI, USA.
The ALS & Neuromuscular Center, UCI Health, Orange, CA, USA.
Trinity College, Beaumont Hospital, Dublin, Ireland.
St. Louis University, St. Louis, MO, USA.
Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Texas Neurology, Dallas, TX, USA.
Royal Brisbane and Women's Hospital, Herston, Australia.
University of Alberta, Edmonton, AB, Canada.
Oregon Health & Science University, Portland, OR, USA.
Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.
Wexner Medical Center, Ohio State University, Columbus, OH, USA.
University of Calgary, Calgary, AB, Canada.
St. Joseph's Hospital and Medical Center, Neurological Institute, AZ, USA Barrow Phoenix.
Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.
Hospital San Rafael, Madrid, Germany.
Perron Institute, Department of Neurology, Fiona Stanley Hospital, The University of Notre Dame Australia, Murdoch University, Perth, Australia.
Mayo Clinic Florida, Jacksonville, FL, USA.
Neurology Associates, Lincoln, NE, USA.
Cleveland Clinic, Cleveland, OH, USA.
University of Florida, Jacksonville, FL, USA.
University of Colorado Denver, Aurora, CO, USA.
University of Chicago Medical Center, Chicago, IL, USA.
University of Saskatchewan, Saskatoon, SK, Canada.
Flinders Medical Centre, Bedford Park, Australia.
London Health Sciences Centre, London, ON, Canada.
Penn State Hershey Medical Center, Hershey, PA, USA.
University of Kansas Medical Center, Kansas City, KS, USA.
West Virginia University, Morgantown, WV, USA.
University of Iowa, Iowa City, IA, USA.
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands.
University of South Florida, Tampa, FL, USA.
Westmead Hospital, Sydney, Australia.
University of Washington, Seattle, WA, USA.
Duke University School of Medicine, Durham, NC, USA.
University of Florida, Gainesville, FL, USA.
ALS/Neuromuscular Clinic Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

Abstract

Objective

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)

中文翻译：

Reldesemtiv 在 ALS 患者中的 2 期、双盲、随机、剂量范围试验

摘要

客观的

评估reldesemtiv在 12 周内对肌萎缩侧索硬化 (ALS) 患者的安全性、剂量反应和初步疗效。方法：直立肺活量 (SVC) ≥ 60 % 缓慢的患者（自诊断后≤ 2 年）按 1:1:1:1 随机分配至reldesemtiv 150、300或 450 mg 每天两次（bid）或安慰剂；积极治疗 12 周，随访 4 周。主要终点是 12 周时预测 SVC 百分比的变化；次要措施包括 ALS 功能评定量表修订版 (ALSFRS-R) 和肌肉力量超级评分。结果：患者（N = 458）被纳入；85% 完成了 12 周的治疗。主要分析未能达到统计显着性（p = 0.11); 次要终点显示没有统计学上的显着影响（ALSFRS-R，p = 0.09；肌肉力量超级分数，p = 0.31）。将所有接受过 reldesemtiv治疗的患者与安慰剂进行汇总的事后分析显示所有终点（SVC、ALSFRS-R 和肌肉力量超级评分的进展率（标称 p 值分别为 0.10、0.01 和 0.20）的进展趋势）。Reldesemtiv耐受性良好，恶心和疲劳是最常见的副作用。注意到估计肾小球滤过率呈剂量依赖性下降，并且在大约 5% 的患者中观察到转氨酶升高。研究药物停药后，肝脏和肾脏异常均趋于消退。结论：虽然主要疗效分析没有显示出统计学意义，但对于所有三个终点都有利于reldesemtiv 的趋势，效应量通常被认为具有临床重要性。耐受性好；轻度肝肾异常是可逆的。应在关键的 3 期试验中评估reldesemtiv对 ALS 患者的影响。（ClinicalTrials.gov 标识符：NCT03160898）

更新日期：2020-09-24

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