Effect of armodafinil on cortical activity and working memory in patients with residual excessive sleepiness associated with CPAP-Treated OSA: a multicenter fMRI study

Abstract

Study objective: To assess the effect of armodafinil on task-related prefrontal cortex activation using functional magnetic resonance imaging (fMRI) in patients with obstructive sleep apnea (OSA) and excessive sleepiness despite continuous positive airway pressure (CPAP) therapy.

Methods: This 2-week, multicenter, prospective, randomized, double-blind, placebo-controlled, parallel-group study was conducted at five neuroimaging sites and four collaborating clinical study centers in the United States. Patients were 40 right-handed or ambidextrous men and women aged between 18 and 60 years, with OSA and persistent sleepiness, as determined by multiple sleep latency and Epworth Sleepiness Scale scores, despite effective, stable use of CPAP. Treatment was randomized (1:1) to once-daily armodafinil 200 mg or placebo. The primary efficacy outcome was a change from baseline at week 2 in the volume of activation meeting the predefined threshold in the dorsolateral prefrontal cortex during a 2-back working memory task. The key secondary measure was the change in task response latency.

Results: No significant differences were observed between treatment groups in the primary or key secondary outcomes. Armodafinil was generally well tolerated. The most common adverse events (occurring in more than one patient [5%]) were headache (19%), nasopharyngitis (14%), and diarrhea (10%).

Conclusions: Armodafinil did not improve fMRI-measured functional brain activation in CPAP-treated patients with OSA and excessive sleepiness.

Study registration: Double-Blind, Placebo-Controlled, Functional Neuroimaging Study of Armodafinil (200 mg/Day) on Prefrontal Cortical Activation in Patients With Residual Excessive Sleepiness Associated With Obstructive Sleep Apnea/Hypopnea.

Trial registration: ClinicalTrials.gov NCT00711516.

Keywords: 2-back task; Armodafinil; cortical activation; excessive sleepiness; functional magnetic resonance imaging; neuroimaging; obstructive sleep apnea.

Figure 1. Study design.

Figure 2. Patient disposition.

Figure 3. Significance maps of the 2-back vs. sustained attention task contrast (all subjects, all visits) projected onto the inflated cortical surface and thresholded at p < 0.05, cluster-wise corrected for multiple comparisons.

Yellow indicates that the amplitude of the 2-back hemodynamic response was greater than that of sustained attention task; blue/cyan indicates the opposite polarity. The green line is the definition of dorsolateral prefrontal cortex for this study.

Figure 4. Significance maps of the 2-back vs. sustained attention task contrast at baseline and final visit for each group.

(A) Group hemodynamic response: right hemisphere lateral view. (B) Group hemodynamic response: right mid-sagittal view. The maps are thresholded at p < 0.01 (uncorrected for multiple comparisons). Red/ yellow indicates that the amplitude of the 2-back hemodynamic response was greater than that of sustained attention task; blue/cyan indicates the opposite polarity.

Figure 5. Mean (SEM [standard error of the mean]) change from baseline in functional activation volume (1 mm³) meeting threshold in DLPFC (dorsolateral prefrontal cortex) on fMRI (functional magnetic resonance imaging).

Change from baseline with armodafinil vs. placebo, p = 0.74, Wilcoxon rank sum test.