Journal article
Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial
JAMA network open, Vol.8(2), e2459058
02/03/2025
DOI: 10.1001/jamanetworkopen.2024.59058
PMCID: PMC11833520
PMID: 39960672
Abstract
The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.
To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS.
Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens.
Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing.
The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164).
Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified.
In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources.
ClinicalTrials.gov Identifier: NCT04297683.
Details
- Title: Subtitle
- Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial
- Creators
- Sabrina Paganoni - Harvard UniversityChristina N Fournier - Emory UniversityEric A Macklin - Harvard UniversityLori B Chibnik - Harvard UniversityMelanie QuintanaBenjamin R SavilleMichelle A DetryMatteo VestrucciJoe MarionAnna McGlothlinSenda Ajroud-Driss - Northwestern UniversityMarianne Chase - Harvard UniversityLindsay Pothier - Harvard UniversityBrittney A Harkey - Harvard UniversityHong Yu - Massachusetts General HospitalAlexander V Sherman - Harvard UniversityJeremy M Shefner - Barrow Neurological InstituteMeghan Hall - Barrow Neurological InstituteGale Kittle - Barrow Neurological InstituteJames D Berry - Massachusetts General HospitalSuma Babu - Harvard UniversityJinsy Andrews - Columbia UniversityDerek Dagostino - Harvard Medical SchoolEric Tustison - Harvard UniversityElisa Giacomelli - Harvard UniversityErica Scirocco - Massachusetts General HospitalGustavo Alameda - Holy Cross HospitalEduardo Locatelli - Holy Cross HospitalDoreen Ho - Harvard UniversityAdam Quick - The Ohio State UniversityJonathan Katz - California Pacific Medical CenterDaragh Heitzman - Texas NeurologyStanley H Appel - Houston MethodistSheetal Shroff - Houston MethodistKevin Felice - Hospital for Special CareNicholas J Maragakis - Johns Hopkins MedicineZachary Simmons - Penn State Milton S. Hershey Medical CenterTimothy M Miller - Hope Center for Neurological DisordersNicholas Olney - Oregon ClinicMichael D Weiss - University of Washington Medical CenterStephen A Goutman - University of MichiganJoseph Americo Fernandes - University of Nebraska Medical CenterOmar Jawdat - University of Kansas Medical CenterMargaret Ayo Owegi - University of Massachusetts Chan Medical SchoolLaura A Foster - University of Colorado DenverTuan Vu - University of South FloridaHristelina IlievaDaniel S Newman - Henry Ford Health SystemXimena Arcila-Londono - Henry Ford Health SystemCarlayne E Jackson - The University of Texas Health Science Center at San AntonioShafeeq Ladha - Barrow Neurological InstituteTerry Heiman-Patterson - Temple UniversityJames B Caress - Wake Forest UniversityAndrea Swenson - University of IowaAmanda Peltier - Vanderbilt University Medical CenterRichard Lewis - Cedars-Sinai Medical CenterDominic Fee - Medical College of WisconsinMatthew Elliott - University of VirginiaRichard Bedlack - Duke UniversityEdward J Kasarskis - University of KentuckyLauren Elman - University of PennsylvaniaJeffrey Rosenfeld - Loma Linda UniversityDavid Walk - University of MinnesotaCourtney McIlduff - Beth Israel Deaconess Medical CenterPaul Twydell - Spectrum HealthEufrosina Young - SUNY Upstate Medical UniversityKristin Johnson - Ochsner Health SystemKourosh Rezania - University of ChicagoNamita A Goyal - University of California, Irvine Medical CenterJeffrey A Cohen - Dartmouth–Hitchcock Medical CenterMichael Benatar - University of MiamiVovanti Jones - University of MissouriJonathan Glass - Emory UniversityJaimin Shah - Mayo Clinic in FloridaSaid R Beydoun - University of Southern CaliforniaJames P Wymer - University of FloridaLindsay Zilliox - University of Maryland, BaltimoreShakti Nayar - Georgetown UniversityGary L PatteeJennifer Martinez-Thompson - Mayo ClinicBrittany HarveyShital PatelPaul Mahoney - University College BirminghamPetra W DudaMerit E Cudkowicz - Massachusetts General HospitalHEALEY ALS Platform Trial Study Group
- Resource Type
- Journal article
- Publication Details
- JAMA network open, Vol.8(2), e2459058
- DOI
- 10.1001/jamanetworkopen.2024.59058
- PMID
- 39960672
- PMCID
- PMC11833520
- NLM abbreviation
- JAMA Netw Open
- ISSN
- 2574-3805
- eISSN
- 2574-3805
- Publisher
- AMER MEDICAL ASSOC
- Grant note
- AMG Charitable FoundationTackle ALSALS AssociationALS Finding a CureMDAALS ONEArthur M. Blank Family FoundationI AM ALSTambourine ALS Collaborative CohortUCB
The HEALEY ALS Platform Trial was supported by the AMG Charitable Foundation, Tackle ALS, the ALS Association, ALS Finding a Cure, MDA, ALS ONE, Arthur M. Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative Cohort, and many other community fundraising initiatives and donors. Study drug and partial funding was provided by UCB.
- Language
- English
- Date published
- 02/03/2025
- Academic Unit
- Neurology
- Record Identifier
- 9984790992802771
Metrics
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