Armodafinil for the treatment of excessive sleepiness associated with mild or moderate closed traumatic brain injury: a 12-week, randomized, double-blind study followed by a 12-month open-label extension

Abstract

Objective: To evaluate the efficacy and tolerability of armodafinil in patients with excessive sleepiness following mild or moderate closed traumatic brain injury (TBI).

Design: Randomized, placebo-controlled, double-blind trial followed by open-label extension.

Setting: 40 US centers.

Patients: Adults with closed TBI (N = 117), Glasgow Coma Scale score >8 at time of injury; baseline Epworth Sleepiness Scale (ESS) ≥10; sleep latency <8 minutes on multiple sleep latency test (MSLT); and Clinical Global Impression-Severity of Illness (CGI-S) score ≥4 for excessive sleepiness.

Intervention: Patients received armodafinil (50, 150, or 250 mg/day) or placebo for 12 weeks followed by an optional 12-month open-label extension.

Measurements and results: Outcomes included MSLT, ESS, Clinical Global Impression-Change (CGI-C), TBI-Work Instability Scale (TBI-WIS), CGI-S, and tolerability. The study was terminated early due to low enrollment. Patients receiving 250 mg armodafinil showed significant improvement in sleep latency from baseline to final visit versus placebo (+7.2 minutes vs. +2.4 minutes; p = 0.0010). CGI-C ratings were much/ very much improved in approximately 50% of patients receiving 150 and 250 mg armodafinil, compared to 38% on placebo. ESS and TBI-WIS scores were not significantly different between groups. In the open-label extension (N = 49), patients demonstrated gradual improvement in ESS, TBI-WIS, and CGI-S scores up to 48 weeks post-baseline. Armodafinil was generally well tolerated, with headache the most common adverse event in both double-blind and open-label portions.

Conclusions: Armodafinil 250 mg significantly improved sleep latency in patients with excessive sleepiness associated with mild or moderate TBI. Efficacy and tolerability of armodafinil were sustained throughout the open-label extension.

Trial registration: NCT00893789, NCT00983437.

Keywords: armodafinil; excessive sleepiness; traumatic brain injury.

Figure 1. Patient disposition for double-blind phase and open-label extension phase.

During the randomized phase of the study, other = patient (placebo) and patient (armodafinil 150 mg/day) who were discontinued because of taking an excluded concomitant medication. The most common reason for discontinuation during the open-label extension (*Other) was the early termination of the study by the sponsor (n = 24).

Figure 2. Mean sleep latency as measured by MSLT in double-blind phase.

MSLT indicates multiple sleep latency test, and ANCOVA indicates analysis of covariance. * p ≤ 0.001, ^† p < 0.05 for comparison of mean change from baseline in MSLT between treatment group and placebo from ANCOVA. ^‡ Final visit, Week 12 or last post-baseline assessment.

Figure 3. Percentage of CGI-C responders (categorized as “Much Improved” or “Very Much Improved”) in double-blind phase.

CGI-C indicates Clinical Global Impression-Change. * p < 0.05 for comparison between treatment group and placebo from Pearson χ² test. ^† Final visit, Week 12, or last post-baseline assessment.