DENVER – The investigational drug armodafinil significantly increased daytime wakefulness in patients with obstructive sleep apnea who experienced excessive sleepiness despite regular nighttime continuous positive airway pressure therapy, according to the results of two phase III clinical trials presented at the annual meeting of the Associated Professional Sleep Societies.
Based on these findings, as well as data from two other phase III trials involving patients with shift work sleep disorder or narcolepsy, the drug's manufacturer, Cephalon Inc., has filed a new drug application seeking approval to market armodafinil (Nuvigil) as a wakefulness-promoting agent in patients with any of three disorders: obstructive sleep apnea-hypopnea syndrome, narcolepsy, or shift work sleep disorder.
Armodafinil is a single-isomer formulation of Cephalon's Provigil (modafinil), which has a markedly shorter half-life than the newer enantiomer.
Dr. Jed E. Black reported on 392 patients with excessive daytime sleepiness as defined by a baseline Epworth Sleepiness Scale score of 10 or more despite good adherence to continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea-hypopnea syndrome. Participants were randomized to armodafinil at 150 mg, 250 mg, or placebo once daily in the morning in this 12-week, double-blind multicenter trial.
Patients on both doses of armodafinil showed significantly improved daytime wakefulness, compared with placebo patients, as measured with the Maintenance of Wakefulness Test at weeks 4, 8, and 12.
Moreover, at each assessment, blinded physicians rated the armodafinil-treated patients as showing significantly more clinical improvement. For example, at the final visit, physicians rated 71% of patients in the 150-mg armodafinil group and 74% in the 250-mg group as showing at least minimal clinical improvement on the Clinical Global Impression of Change (CGIC) scale compared with 37% of patients taking placebo.
From a mean baseline Epworth Sleepiness Scale score of 15.5, the armodafinil group (both dosages combined) improved by a mean of 5.5 points, compared with 3.3 points in the placebo group. The armodafinil-treated patients rated their global fatigue as improved by a mean of 1.2 points from a baseline of 4.9 on the Brief Fatigue Inventory; that was twice as great a gain as in the placebo arm, said Dr. Black of Stanford (Calif.) University.
Armodafinil had no adverse effects on nighttime sleep as assessed by polysomnography, nor did it affect CPAP use, which continued at an average of 7 hours per night throughout the study.
Results were similar in a separate phase III trial reported by Max Hirshkowitz, Ph.D. This double-blind study included 259 patients with obstructive sleep apnea-hypopnea syndrome randomized to 150 mg of armodafinil or placebo for 12 weeks. These patients were experiencing excessive daytime sleepiness despite averaging nearly 7 hours per night of CPAP.
Once again, armodafinil resulted in significantly improved objective and subjective measures of wakefulness. In this trial, however, 150 mg/day of armodafinil also significantly improved the quality of long-term episodic memory, although it didn't affect measures of attention or speed of memory, according to Dr. Hirshkowitz of the Michael E. DeBakey Veterans Affairs Medical Center, Houston.
In both trials, the adverse events that were more common with armodafinil than placebo were mild to moderate headache, nausea, insomnia, dizziness, and anxiety. Headache and nausea, the two most frequent adverse events, were dose related. Headache, for example, occurred in 21% of patients on 250 mg/day of armodafinil in the first trial, in 15% of those on 150 mg/day in both trials, and in 7%–8% of patients on placebo.
Both phase III clinical trials were sponsored by Cephalon Inc.
