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 multi-center trial with an adaptive, two-stage, biasadjusted, randomized, placebo-controlled, double-blind, Phase II design (n=185). The primary outcome in both stages was 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 Kaufmann et al. Page 2Ann Neurol. Author manuscript; available in PMC 2010 August 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript accompanying pre-specified sensitivity test, and further supplementary analyses. Pre-specified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns.Interpretation-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.ALS is an orphan disease with an average annual incidence rate of 1 to 2 per 100,000 person-years, 1-3 and, because the disease typically leads to death within 2 to 4 years of onset, 4 a relatively low prevalence of 4-6 per 100,000 people. 5 About 10% of ALS cases are familial, and about 15 to 20% of autosomal dominant familial ALS patients have mutations the superoxide dismutase 1 (SOD1) gene. 6 The pathogenesis remains incompletely understood, but several lines of evidence suggest that oxidative stress plays an important role. SOD 1 is an enzyme that plays a role in detoxifying free radicals 7 . In a transgenic mouse model of familial ALS, there is increased oxidative stress. 8 In patients with sporadic ALS, oxidative stress indicators were found in plasma, urine, and CSF. 9-13 Mitochondrial impairment in ALS is supported by several findings in vitro, animal studies, and patients. In an ALS cell culture model, motor neuron cell lines harboring SOD1 mutations have morphologically abnormal mitochondria and impaired respiratory chain function. 14 Respiratory chain dysfunction has also been described in an ALS mouse model. 15 In spinal cord tissue of ALS patients, mutant mtDNA molecules were incre...

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“…The final results of this study have not been published yet. Similarly, disappointing results are obtained in a phase II trial evaluating the efficacy of 1.8 g/day and 2.7 g/day of CoQ 10 for amyotrophic lateral sclerosis (Kaufmann et al, 2009). …”

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

“…A futility design involves a predetermined threshold for benefit. A large, costly efficacy trial may be avoided if this threshold is not met, as seen in the coenzyme Q10 trial in ALS [78]. Futility stopping rules and a time-to-event design in a randomized trial of lithium in ALS ensured speedy enrollment before halting of the trial for futility at the first interim analysis [8].…”

Designing Clinical Trials for Dystonia

“…This design also suffers from a lack of blinding and absence of a concurrent control group, although a randomized control group can be included [37]. Another design, which has recently been utilized in trials for neurodegenerative diseases, is the futility design [38][39][40][41][42]. The objective of a trial with a futility design is not to demonstrate that an intervention is efficacious, but rather to demonstrate that it is futile and not worth further study.…”

“…Because no formal hypothesis testing is performed, the required sample size is much smaller in selection designs than in conventional parallel group designs that formally evaluate the statistical significance of group differences. Selection designs can also be used in a sequential manner, where in an initial stage the "best" agent or dosage is chosen and then used in a superiority or futility design in the second stage of the trial [41]. Such adaptive designs are discussed below.…”