title: Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.
abstract: OBJECTIVE
  Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial.
  
  
  METHODS
  We designed and implemented a multicenter trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n = 185). The primary outcome in both stages was a decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo.
  
  
  RESULTS
  Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying prespecified sensitivity test, and further supplementary analyses. Prespecified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns.
  
  
  CONCLUSIONS
  CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial.
authors.affiliation: Department of Neurology, Clinical Coordinating Center, Columbia University, New York, NY 10032, USA. pk88@columbia.edu
authors.forename: Petra
authors.initials: P
authors.lastname: Kaufmann
authors.forename: John L P
authors.initials: JL
authors.lastname: Thompson
authors.forename: Gilberto
authors.initials: G
authors.lastname: Levy
authors.forename: Richard
authors.initials: R
authors.lastname: Buchsbaum
authors.forename: Jeremy
authors.initials: J
authors.lastname: Shefner
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Krivickas
authors.forename: Jonathan
authors.initials: J
authors.lastname: Katz
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Rollins
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barohn
authors.forename: Carlayne E
authors.initials: CE
authors.lastname: Jackson
authors.forename: Ezgi
authors.initials: E
authors.lastname: Tiryaki
authors.forename: Catherine
authors.initials: C
authors.lastname: Lomen-Hoerth
authors.forename: Carmel
authors.initials: C
authors.lastname: Armon
authors.forename: Rup
authors.initials: R
authors.lastname: Tandan
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Rudnicki
authors.forename: Kourosh
authors.initials: K
authors.lastname: Rezania
authors.forename: Robert
authors.initials: R
authors.lastname: Sufit
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: Steven P
authors.initials: SP
authors.lastname: Novella
authors.forename: Terry
authors.initials: T
authors.lastname: Heiman-Patterson
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kasarskis
authors.forename: Erik P
authors.initials: EP
authors.lastname: Pioro
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Montes
authors.forename: Rachel
authors.initials: R
authors.lastname: Arbing
authors.forename: Darleen
authors.initials: D
authors.lastname: Vecchio
authors.forename: Alexandra
authors.initials: A
authors.lastname: Barsdorf
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsumoto
authors.forename: Bruce
authors.initials: B
authors.lastname: Levin
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000401:mortality; D000975:Antioxidants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D014451:Ubiquinone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D014451:Ubiquinone; C024989:coenzyme Q10