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. 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.

Vagal nerve stimulation: clinical and electrophysiological effects on vocal fold function.

More than 16,000 vagal nerve stimulators (VNSs) have been implanted for refractory epileptic seizures. The most commonly reported side effect is hoarseness. This study examines the effects of VNS placement on vocal fold function. Eleven patients who had undergone VNS placement at our institution were recruited. Subjective evaluation by a panel of speech and language pathologists of both connected speech and videolaryngoscopy recordings were used both at rest and during VNS activation. Additional subjective evaluation included use of the Voice Handicap Index for the study group. These results were compared to data from age- and sex-matched controls. Objective data included maximum phonation time in the study and control groups, as well as laryngeal electromyography performed on the VNS-implanted patients only. Motor unit potential morphology and recruitment, as well as spontaneous activity, were analyzed bilaterally for the cricothyroid and thyroarytenoid muscles. Significant differences were found between the study and control groups subjectively for vocal quality and videolaryngoscopy parameters. Vocal fold tension, supraglottic muscular hyperfunction, and reduced vocal fold mobility were the most common findings during VNS activation. Two of 10 patients had immobile left vocal folds in the absence of active stimulation. The maximum phonation time was generally reduced in the subject group, but this reduction did not reach statistical significance. Finally, 6 of 10 patients had abnormal electromyographic results, including large-amplitude polyphasic motor unit potentials and decreased recruitment. We conclude that implantation of a VNS can affect vocal fold function. The effects are magnified during periods of active stimulation. There is the potential for nerve degeneration after prolonged repetitive stimulation, and there may be a trend toward greater vocal fold dysfunction with higher stimulation parameters.