Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: A 12-week, multicenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults

Background: Some patients with obstructive sleep apnea/hypopnea syndrome (OSA/HS) experience excessive sleepiness (ES) that might not resolve with nasal continuous positive airway pressure (nCPAP) treatment. Objective: The aim of the present study was to assess the efficacy and tolerability of armodafinil 150 or 250 mg QD when used as adjunctive treatment for residual ES associated with OSA/HS in patients who are adherent to nCPAP therapy. Methods: This 12-week, multicenter, double-blind, randomized, placebo-controlled study was conducted at 37 centers in the United States and Canada. Male and female patients aged 18 to 65 years with residual ES associated with OSA/HS were enrolled. Patients were randomly assigned to receive armodafinil 150 or 250 mg or placebo PO QD for 12 weeks. Assessments were conducted at baseline and study weeks 4, 8, and 12 and included the Maintenance of Wakefulness Test (MWT) to determine wakefulness, the Clinical Global Impression of Change (CGI-C) to determine improvement in clinical condition, the Epworth Sleepiness Scale (ESS) to determine patient-estimated wakefulness, the Brief Fatigue Inventory (BFI) to determine global fatigue, and the Cognitive Drug Research computerized assessment battery. To distinguish between earlier and later effects, sleep latencies, assessed using the MWT, were averaged across the first 4 (9 and 11 AM, and 1 and 3 P. vi) and last 3 (3, 5, and 7 Pm) tests. Tolerability assessments included monitoring of adverse events (AEs), clinical laboratory tests, vital sign measurements, and electrocardiography. Results: A total of 395 patients were enrolled in the study (armodafinil 1.50 mg/d, 133; armodafinil 250 mg/d, 131; placebo, 131); 392 received >= 1 dose of study drug (armodafinil 150 mg/d, 131; armodafinil 250 mg/d, 131; placebo, 130). The armodafinil and placebo groups were well matched with regard to age (mean [SD], 49.2 [8.9] vs 50.1 [9.4] years), sex (71% vs 69% men), race (84% vs 87% white), and body weight (mean [SD], 110.3 [24.9] vs 111.9 [24.0] kg). At the final visit, the mean (SD) change from baseline in MWT sleep latency across the morning and afternoon was significantly greater in the armodafinil combined group compared with the placebo group (+1.9 [7.3] vs -1.7 [8.6] minutes; P < 0.001). Also at the final visit, the proportions of patients who showed at least minimal improvement on the CGI-C, and the mean (SD) changes from baseline in ESS and BFI scores, were significantly greater in the armodafinil group compared with those in the placebo group (72% vs 37%, -5.5 [5.0] vs -3.3 [4.7], and -1.2 [2.2] vs -0.6 [2.0], respectively; P < 0.001, P < 0.001, and P < 0.01, respectively). No significant effects on nighttime sleep, as assessed using polysomnography, were found with armodafinil. AEs reported in the armodafinil combined and placebo groups were headache, nausea, insomnia, anxiety, and dizziness. Serious AEs (ulcerative colitis, migraine, worsening of Axis 11 and mood disorder, and duodenal ulcer) were reported in 4 (1.5%) patients receiving armodafinil and were considered by the investigator not or unlikely to be drug related. Conclusions: In this selected population of patients with OSA/HS and residual ES despite effective treatment with nCPAP, armodafinil QD used as an adjunct to nCPAP treatment was associated with improved wakefulness and overall clinical condition. Clinical benefit was shown at the first assessment and maintained for the 12-week duration of the study. Armodafinil was also associated with significantly reduced interference of ES with daily activities and global fatigue. Armodafinil was well tolerated, with no adverse effect on nighttime sleep or nCPAP use.