CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.
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Writing Committee for the HEALEY ALS Platform Trial, Berry James D, Maragakis Nicholas J, Macklin Eric A, Chibnik Lori B, Quintana Melanie, Saville Benjamin R, Detry Michelle A, Vestrucci Matteo, Marion Joseph, McGlothlin Anna, Stommel Elijah W, Chase Marianne, Pothier Lindsay, Harkey Brittney A, Yu Hong, Sherman Alex, Shefner Jeremy, Hall Meghan, Kittle Gale, Babu Suma, Andrews Jinsy, D'Agostino Derek, Tustison Eric, Scirocco Erica, Giacomelli Elisa, Alameda Gustavo, Locatelli Eduardo, Ho Doreen, Quick Adam, Ajroud-Driss Senda, Katz Jonathan, Heitzman Daragh, Appel Stanley H, Shroff Sheetal, Felice Kevin J, Simmons Zachary, Miller Timothy, Olney Nicholas, Weiss Michael D, Goutman Stephen A, Fernandes Joseph Americo, Jawdat Omar, Owegi Margaret Ayo, Foster Laura, Vu Tuan, Ilieva Hristelina, Newman Daniel S, Arcila-Londono Ximena, Jackson Carlayne, Ladha Shafeeq, Heiman-Patterson Terry, Caress James, Swenson Andrea, Peltier Amanda, Lewis Richard, Fee Dominic, Elliott Matthew, Bedlack Richard, Kasarskis Edward J, Elman Lauren, Rosenfeld Jeffrey, Walk David, McIlduff Courtney E, Twydell Paul, Young Eufrosina, Johnson Kristin, Rezania Kourosh, Goyal Namita A, Cohen Jeffrey A, Benatar Michael, Jones Vovanti, Glass Jonathan, Shah Jaimin, Beydoun Said R, Wymer James P, Zilliox Lindsay, Nayar Shakti, Pattee Gary L, Martinez-Thompson Jennifer, Rynders Austin, Evan Jacob, Evan Jeremy, Hartford Alan, Sepassi Marjan, Ho Karen S, Glanzman Robert, Greenberg Benjamin, Hotchkin Michael T, Paganoni Sabrina, Cudkowicz Merit E, HEALEY ALS Platform Trial Study Group
Аннотация
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.