Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.
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.
Kaufmann
Petra
P
Department of Neurology, Clinical Coordinating Center, Columbia University, New York, NY 10032, USA. pk88@columbia.edu
Thompson
John L P
JL
Levy
Gilberto
G
Buchsbaum
Richard
R
Shefner
Jeremy
J
Krivickas
Lisa S
LS
Katz
Jonathan
J
Rollins
Yvonne
Y
Barohn
Richard J
RJ
Jackson
Carlayne E
CE
Tiryaki
Ezgi
E
Lomen-Hoerth
Catherine
C
Armon
Carmel
C
Tandan
Rup
R
Rudnicki
Stacy A
SA
Rezania
Kourosh
K
Sufit
Robert
R
Pestronk
Alan
A
Novella
Steven P
SP
Heiman-Patterson
Terry
T
Kasarskis
Edward J
EJ
Pioro
Erik P
EP
Montes
Jacqueline
J
Arbing
Rachel
R
Vecchio
Darleen
D
Barsdorf
Alexandra
A
Mitsumoto
Hiroshi
H
Levin
Bruce
B
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
D000975:Antioxidants; D014451:Ubiquinone; C024989:coenzyme Q10