Introduction 1 2 1 2 3 4 5 6 7 8 1 9 10 11 12 18 12 15 17 7 R S 19 20 R S 21 23 24 25 26 27 26 27 Materials and methods Study design and procedures 26 27 26 27 28 n n 26 n n n 27 ® Patient selection criteria 26 27 International Classification of Sleep Disorders 1 29 30 Patient exclusion criteria 31 Assessments Efficacy assessments 32 33 29 34 35 36 30 30 37 Safety and tolerability assessments Adverse events were monitored and recorded by the study investigators at each center throughout both studies. Clinical laboratory tests (blood chemistry, hematology, urinalysis), vital signs (resting heart rate and systolic and diastolic blood pressure 3 and 13 h postadministration), and electrocardiograms were obtained at screening, baseline, and weeks 4, 8, and 12. Physical examinations were performed at baseline and week 12. Patients’ use of nCPAP was monitored at least 2 weeks before baseline and throughout both studies using the Respironics REMstar Auto CPAP system. Effect on nighttime sleep was determined by PSG, which was performed the night immediately after the measurement of daytime MWT during the second screening visit and the final visit. The PSG was conducted for 8 h, starting within 30 min of the patient’s usual bedtime but not earlier than 21:30. Clinically significant elevations in resting systolic and diastolic blood pressure were defined a priori as greater than or equal to 140 mmHg with an increase of greater than or equal to 10% and greater than or equal to 90 mmHg with an increase of greater than or equal to 10%, respectively. Patients with worsening hypertension included those who had a history of hypertension at baseline and who started new antihypertensive medication and/or increased the dose of previously used antihypertensive medication during the studies. Patients with newly diagnosed hypertension included those who had no history of hypertension at baseline and who started antihypertensive medication during the studies. Patients at risk for hypertension included those who had at least two clinically significant elevations in blood pressure readings between baseline and final visit. Statistical analysis Descriptive statistics were used to summarize continuous and categorical demographic variables. Efficacy assessments were analyzed at weeks 4, 8, and 12 using observed cases and at final visit (week 12 or last postbaseline measurement) using the last observation carried forward approach. Efficacy analyses included randomized patients who received at least one dose of study drug and had a baseline measurement with at least one postbaseline measurement on the MWT and CGI-C. Safety and tolerability analyses included all randomized patients who received at least one dose of study drug. All efficacy assessments were analyzed by analysis of variance (ANOVA) with treatment and study as factors. Tests of poolability for all continuous efficacy variables across the two studies were conducted using an ANOVA with treatment and study and treatment by study interaction as factors. Vital signs and data from nighttime PSG were analyzed by Wilcoxon rank-sum test. For nCPAP use, the change from baseline to on-treatment values was analyzed using one-way ANOVA. All statistical tests were two-tailed, and the 5% level of significance was used. Results Patient demographics and disease characteristics 1 1 2 Fig. 1 Patient disposition  Table 1 Patient demographics and baseline characteristics Characteristic n n Age (years) Mean (SD) 49.7 (9.0) 50.3 (9.1) n Men 283 (72) 183 (70) Women 108 (28) 77 (30) n White 327 (84) 224 (86) Black 36 (9) 21 (8) Asian 6 (2) 3 (1) Other 22 (6) 11 (4) Missing 0 1 (<1) Weight (kg) Mean (SD) 110.4 (24.6) 111.2 (23.7) 2 Mean (SD) 36.4 (8.0) 36.9 (7.5) n Moderately ill 219 (56) 138 (53) Markedly, severely, or extremely ill 172 (44) 122 (47) nCPAP (h) Mean (SD) 6.9 (1.2) 6.9 (1.0) AHI Mean (SD) 1.5 (3.3) 1.2 (2.1) History of hypertension n 159 (41) 108 (42) AHI BMI CGI-S nCPAP Effects on wakefulness 2 P Fig. 2 a b  2 P Effects on memory and attention P 3 P Fig. 3 a b  P 3 P Effects on patients’ ability to engage in activities 1 P 4 Fig. 4 Mean (SEM) change from baseline in Epworth Sleepiness Scale total score  Effects on fatigue P 5 P 5 P Fig. 5 a b BFI  Safety and tolerability 2 n n n n n n Table 2 Adverse events occurring in ≥5% of patients n n n Headache 65 (17) 20 (8) Nausea 22 (6) 10 (4) Insomnia 22 (6) 3 (1) Dizziness 19 (5) 4 (2) Anxiety 20 (5) 2 (<1) There were no clinically significant changes from baseline to final visit in either the armodafinil group or the placebo group for laboratory values, electrocardiogram parameters, or physical examinations. There were also no meaningful changes (clinical or statistical) from baseline to final visit for systolic blood pressure (0.2 [14.2] mmHg for armodafinil vs −1.0 [14.6] mmHg for placebo), diastolic blood pressure (0.3 [9.3] mmHg for armodafinil vs −1.0 [10.0] mmHg for placebo), and heart rate (2.3 [9.6] bpm for armodafinil vs 1.4 [9.6] bpm for placebo). The incidence of patients with newly diagnosed hypertension was less than 1% in the armodafinil group and less than 1% in the placebo group. The proportion of patients at risk for hypertension was similar for both treatment groups (18% of 391 patients, armodafinil group; 16% of 260 patients, placebo group). The incidence of patients with worsening hypertension was 3% of 391 patients in the armodafinil group and 2% of 260 patients in the placebo group. P P P 3 Table 3 a Variable (units), mean (SD) n n Baseline Final Visit Baseline Final Visit Latency to persistent sleep (min) 22.3 (26.9) 19.6 (20.5) 21.3 (24.0) 20.8 (21.4) n 20.0 (11.3) 18.5 (10.2) 18.7 (9.7) 18.4 (10.4) n 8.8 (4.7) 9.2 (5.3) 8.7 (5.1) 9.6 (5.4) Sleep efficiency (%) 82.4 (10.9) 82.0 (12.0) 82.0 (12.1) 81.4 (11.2) Wake after sleep onset (min) 66.6 (43.9) 69.1 (48.5) 68.7 (50.3) 70.2 (46.5) Stage 1 (%) 11.2 (6.4) 10.5 (5.5) 10.9 (6.1) 10.6 (6.2) Stage 2 (%) 59.3 (9.8) 58.8 (11.2) 58.8 (10.1) 57.7 (11.2) Stage 3/4 (%) 10.6 (9.0) 10.3 (9.0) 10.8 (9.6) 10.9 (10.2) REM (%) 18.9 (6.9) 19.8 (7.1) 19.5 (7.2) 20.7 (8.0) REM a Discussion 4 6 15 17 6 8 11 18 26 27 38 26 27 17 16 39 41 15 16 40 42 43 26 27 Armodafinil significantly improved patients’ ability to engage in activities of daily living at all visits as measured by the ESS. The patient population studied in this pooled analysis had severe ES (mean ESS score greater than 15) despite effective and regular nCPAP therapy. At the final visit, 49 and 26% of patients receiving armodafinil and placebo, respectively, had ESS scores less than 10, indicating that nearly half of patients no longer had pathological sleepiness with adjunct armodafinil treatment. 44 45 46 26 27 37 24 Findings from the present pooled analysis are limited to patients with OSA who have residual ES despite regular and effective nCPAP therapy and should not be generalized to patients with OSA who are not receiving adequate nCPAP therapy or are not using it regularly. Additionally, the 12-week duration of treatment in these studies limits the applicability of observed results to a longer period of treatment. It should be recognized that armodafinil does not treat the underlying airway obstruction and should not be considered a replacement for nCPAP therapy in patients with OSA. Further research is needed to determine the role armodafinil may have in improving cognitive function and whether the significant reduction in fatigue observed in the pooled analysis will contribute toward improved quality of life in this patient population. In conclusion, pooled data from two 12-week, double-blind, placebo-controlled studies showed that once-daily administration of armodafinil significantly improved wakefulness when used as adjunct therapy in nCPAP-adherent patients with residual ES associated with OSA. The effect on wakefulness with armodafinil was maintained throughout the day. Importantly, adjunctive treatment with armodafinil was associated with significant improvements in long-term memory and patients’ ability to engage in daily activities. Armodafinil significantly reduced fatigue in the studied population and was well tolerated.