Jinsy Andrews, Sabrina Paganoni, Eric A Macklin, Lori B Chibnik, Melanie Quintana, Benjamin R Saville, Michelle A Detry, Matteo Vestrucci, Joseph Marion, Anna McGlothlin, Eufrosina Young, Marianne Chase, Lindsay Pothier, Brittney Harkey, Hong Yu, Alex Sherman, Jeremy Shefner, Meghan Hall, Gale Kittle, Mariah R Connolly, James D Berry, Derek D'Agostino, Eric Tustison, Elisa Giacomelli, Erica Scirocco, Gustavo Alameda, Eduardo Locatelli, Doreen Ho, Adam Quick, Daragh Heitzman, Senda Ajroud-Driss, Stanley H Appel, Sheetal Shroff, Jonathan Katz, Kevin Felice, Nicholas J Maragakis, Zachary Simmons, Stephen A Goutman, Nicholas Olney, Timothy Miller, Joseph Americo Fernandes, Hristelina Ilieva, Omar Jawdat, Michael D Weiss, Laura Foster, Tuan Vu, Shafeeq Ladha, Margaret Ayo Owegi, Daniel S Newman, Ximena Arcila-Londono, Carlayne E Jackson, Andrea Swenson, Terry Heiman-Patterson, James Caress, Dominic Fee, Amanda Peltier, Richard Lewis, Jeffrey Rosenfeld, David Walk, Kristin Johnson, Matthew Elliott, Edward J Kasarskis, Seward Rutkove, Courtney E McIlduff, Richard Bedlack, Lauren Elman, Namita A Goyal, Kourosh Rezania, Paul Twydell, Michael Benatar, Jonathan Glass, Jeffrey A Cohen, Vovanti Jones, Lindsay Zilliox, James P Wymer, Said R Beydoun, Jaimin Shah, Gary L Pattee, Jennifer Martinez-Thompson, Shakti Nayar, Volkan Granit, Mary Donohue, Katheryn Grossman, Daniel J Campbell, Irfan A Qureshi, Merit E Cudkowicz, Suma Babu
{"title":"Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial.","authors":"Jinsy Andrews, Sabrina Paganoni, Eric A Macklin, Lori B Chibnik, Melanie Quintana, Benjamin R Saville, Michelle A Detry, Matteo Vestrucci, Joseph Marion, Anna McGlothlin, Eufrosina Young, Marianne Chase, Lindsay Pothier, Brittney Harkey, Hong Yu, Alex Sherman, Jeremy Shefner, Meghan Hall, Gale Kittle, Mariah R Connolly, James D Berry, Derek D'Agostino, Eric Tustison, Elisa Giacomelli, Erica Scirocco, Gustavo Alameda, Eduardo Locatelli, Doreen Ho, Adam Quick, Daragh Heitzman, Senda Ajroud-Driss, Stanley H Appel, Sheetal Shroff, Jonathan Katz, Kevin Felice, Nicholas J Maragakis, Zachary Simmons, Stephen A Goutman, Nicholas Olney, Timothy Miller, Joseph Americo Fernandes, Hristelina Ilieva, Omar Jawdat, Michael D Weiss, Laura Foster, Tuan Vu, Shafeeq Ladha, Margaret Ayo Owegi, Daniel S Newman, Ximena Arcila-Londono, Carlayne E Jackson, Andrea Swenson, Terry Heiman-Patterson, James Caress, Dominic Fee, Amanda Peltier, Richard Lewis, Jeffrey Rosenfeld, David Walk, Kristin Johnson, Matthew Elliott, Edward J Kasarskis, Seward Rutkove, Courtney E McIlduff, Richard Bedlack, Lauren Elman, Namita A Goyal, Kourosh Rezania, Paul Twydell, Michael Benatar, Jonathan Glass, Jeffrey A Cohen, Vovanti Jones, Lindsay Zilliox, James P Wymer, Said R Beydoun, Jaimin Shah, Gary L Pattee, Jennifer Martinez-Thompson, Shakti Nayar, Volkan Granit, Mary Donohue, Katheryn Grossman, Daniel J Campbell, Irfan A Qureshi, Merit E Cudkowicz, Suma Babu","doi":"10.1001/jamaneurol.2024.5249","DOIUrl":null,"url":null,"abstract":"<p><strong>Importance: </strong>Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.</p><p><strong>Objective: </strong>To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.</p><p><strong>Design, settings, and participants: </strong>Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.</p><p><strong>Interventions: </strong>Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.</p><p><strong>Main outcomes and measures: </strong>The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.</p><p><strong>Results: </strong>A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.</p><p><strong>Conclusions and relevance: </strong>Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.</p><p><strong>Trial registration: </strong>Clinical Trial Identifiers: NCT04297683 and NCT04436510.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":""},"PeriodicalIF":20.4000,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833655/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JAMA neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1001/jamaneurol.2024.5249","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Importance: Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.
Objective: To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.
Design, settings, and participants: Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.
Interventions: Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.
Main outcomes and measures: The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.
Results: A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.
Conclusions and relevance: Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.
Trial registration: Clinical Trial Identifiers: NCT04297683 and NCT04436510.
期刊介绍：
JAMA Neurology is an international peer-reviewed journal for physicians caring for people with neurologic disorders and those interested in the structure and function of the normal and diseased nervous system. The Archives of Neurology & Psychiatry began publication in 1919 and, in 1959, became 2 separate journals: Archives of Neurology and Archives of General Psychiatry. In 2013, their names changed to JAMA Neurology and JAMA Psychiatry, respectively. JAMA Neurology is a member of the JAMA Network, a consortium of peer-reviewed, general medical and specialty publications.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
