• Petra Kaufmann, John L P Thompson, Gilberto Levy, Richard Buchsbaum, Jeremy Shefner, Lisa S Krivickas, Jonathan Katz, Yvonne Rollins, Richard J Barohn, Carlayne E Jackson, Ezgi Tiryaki, Catherine Lomen-Hoerth, Carmel Armon, Rup Tandan, Stacy A Rudnicki, Kourosh Rezania, Robert Sufit, Alan Pestronk, Steven P Novella, Terry Heiman-Patterson, Edward J Kasarskis, Erik P Pioro, Jacqueline Montes, Rachel Arbing, Darleen Vecchio, Alexandra Barsdorf, Hiroshi Mitsumoto, Bruce Levin, and QALS Study Group.
• Department of Neurology, Clinical Coordinating Center, Columbia University, New York, NY 10032, USA. pk88@columbia.edu
• Ann. Neurol. 2009 Aug 1; 66 (2): 235-44.

ObjectiveAmyotrophic 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.MethodsWe 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.ResultsStage 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.InterpretationCoQ10 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.

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