Journal article
CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial
JAMA : the journal of the American Medical Association, Vol.333(13), pp.1138-1149
04/01/2025
DOI: 10.1001/jama.2024.27643
PMCID: PMC11833661
PMID: 40067821
Abstract
IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production. OBJECTIVE: To determine the effects of CNM-Au8 on ALS disease progression. DESIGN, SETTING, AND PARTICIPANTS: CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. INTERVENTIONS: Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. RESULTS: Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). CONCLUSIONS AND RELEVANCE: No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345
Details
- Title: Subtitle
- CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial
- Creators
- James D Berry - Massachusetts General HospitalAndrea Swenson - University of IowaNicholas J Maragakis - Johns Hopkins UniversityEric A Macklin - Harvard UniversityLori B Chibnik - Harvard UniversityMelanie QuintanaBenjamin R SavilleMichelle A DetryMatteo VestrucciJoseph MarionAnna McGlothlinElijah W Stommel - Dartmouth–Hitchcock Medical CenterMarianne Chase - Harvard UniversityLindsay Pothier - Harvard UniversityBrittney A Harkey - Harvard UniversityHong Yu - Harvard UniversityAlex Sherman - Harvard UniversityJeremy Shefner - Barrow Neurological InstituteGale Kittle - Barrow Neurological InstituteMeghan Hall - Barrow Neurological InstituteSuma Babu - Harvard UniversityJinsy Andrews - Columbia University Irving Medical CenterDerek D’Agostino - Harvard UniversityEric Tustison - Harvard UniversityErica Scirocco - Harvard UniversityElisa Giacomelli - Harvard UniversityGustavo Alameda - Holy Cross HospitalEduardo Locatelli - Holy Cross HospitalDoreen Ho - Harvard UniversityAdam Quick - The Ohio State UniversitySenda Ajroud-Driss - Northwestern UniversityJonathan Katz - California Pacific Medical CenterDaragh Heitzman - Texas NeurologyStanley H Appel - Houston MethodistSheetal Shroff - Houston MethodistKevin J Felice - Hospital for Special CareZachary SimmonsTimothy Miller - Washington University in St. LouisNicholas Olney - Oregon ClinicMichael D Weiss - University of WashingtonStephen 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 Foster - University of Colorado Anschutz Medical CampusTuan Vu - University of South FloridaHristelina IlievaDaniel S Newman - Henry Ford HospitalXimena Arcila-Londono - Henry Ford HospitalCarlayne Jackson - The University of Texas Health Science Center at San AntonioShafeeq Ladha - Barrow Neurological InstituteTerry Heiman-Patterson - Temple UniversityJames Caress - Wake Forest UniversityAmanda 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 E McIlduff - Beth Israel Deaconess Medical CenterPaul Twydell - Corewell Health Blodgett HospitalEufrosina 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 ClinicAustin RyndersJacob EvanJeremy EvanAlan HartfordMarjan SepassiKaren S HoRobert GlanzmanBenjamin GreenbergMichael T HotchkinSabrina Paganoni - Spaulding Rehabilitation HospitalMerit E Cudkowicz - Massachusetts General Hospital
- Resource Type
- Journal article
- Publication Details
- JAMA : the journal of the American Medical Association, Vol.333(13), pp.1138-1149
- DOI
- 10.1001/jama.2024.27643
- PMID
- 40067821
- PMCID
- PMC11833661
- NLM abbreviation
- JAMA
- ISSN
- 0098-7484
- eISSN
- 1538-3598
- Publisher
- American Medical Association
- Grant note
- AMG Charitable FoundationTackle ALSALS AssociationALS Finding a CureMuscular Dystrophy AssociationALS ONEArthur M. Blank Family FoundationI AM ALSTambourine ALS CollaborativeClene Nanomedicine
The HEALEY ALS Platform Trial was supported and made possible by the AMG Charitable Foundation, Tackle ALS, The ALS Association, ALS Finding a Cure, Muscular Dystrophy Association, ALS ONE, Arthur M. Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative, and many other community fundraising initiatives and donors. The study drug and partial funding were provided by Clene Nanomedicine.
- Language
- English
- Electronic publication date
- 02/17/2025
- Date published
- 04/01/2025
- Academic Unit
- Neurology
- Record Identifier
- 9984792360602771
Metrics
17 Record Views