Study to Evaluate the Efficacy and Safety of Armodafinil as Treatment for Patients With Excessive Sleepiness Associated With Mild or Moderate Closed Traumatic Brain Injury

A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Fixed-Dosage Study to Evaluate the Efficacy and Safety of Armodafinil (50, 150, and 250 mg/Day) as Treatment for Patients With Excessive Sleepiness Associated With Mild or Moderate Closed Traumatic Brain Injury

The primary objective of the study is to determine whether armodafinil treatment is more effective than placebo treatment in patients with excessive sleepiness associated with mild or moderate closed traumatic brain injury (TBI).

Inclusion Criteria:

• The patient had a mild (Glasgow Coma Scale [GCS] score 13-15) or moderate (GCS score 9-12) closed TBI at the time of the injury, and the injury occurred 1 to 10 years prior to screening.
• The patient had a Glasgow Outcome Scale score of 5 at the screening visit.
• The patient had an Epworth Sleepiness Scale (ESS) score of at least 10 at screening.
• The patient had a mean sleep latency on the Multiple Sleep Latency Test (MSLT) (average of 4 naps) of less than 8 minutes at baseline.
• The patient had a Clinical Global Impression of Severity of Illness (CGI-S) rating relating to their excessive sleepiness of 4 or more at the screening and baseline visits.
• The patient had a complaint of excessive sleepiness (at least 5 days/week on average) for at least 3 months, and the excessive sleepiness began within 12 months of the TBI.
• Written informed consent was obtained.
• The patient was a man or woman of any ethnic origin 18 to 65 years of age.
• If admitted to an inpatient treatment facility, the patient was discharged at least 1 month prior to the screening visit.
• The patient did not have any medical or psychiatric disorders that could account for the excessive sleepiness.
• Women of childbearing potential (not surgically sterile or 2 years postmenopausal), used a medically accepted method of contraception, and continued use of one of these methods for the duration of the study (and for 30 days after participation in the study). Acceptable methods of contraception included: abstinence, barrier method with spermicide, steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method, or intrauterine device (IUD).
• The patient was in otherwise good health, as judged by the investigator, on the basis of a medical and psychiatric history, physical examination, electrocardiogram (ECG), serum chemistry, hematology, and urinalysis.
• The patient was willing and able to comply with study restrictions and to attend regularly scheduled clinic visits as specified in this protocol.
• The patient had a Mini Mental State Examination (MMSE) score of more than 26 at the screening visit.
• The patient was on stable dosages of medications (allowed by the protocol) for a minimum of 3 months (selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]), 8 weeks (contraceptives), or 4 weeks (all other allowed medication) before the screening visit and was not likely to require a change in therapy for at least 12 weeks on the basis of the investigators' assessment.
• The patient had a habitual bedtime between 2100 and 2400.
• The patient had no other head injuries that, based on medical record documentation or history from the patient and reliable informant (if available), were temporally related to the onset or to any worsening of excessive sleepiness.
• The patient had no other head injury fulfilling the criteria for TBI within ±1 year of the TBI identified according to criterion (a1).

Exclusion Criteria:

• The patient had a history of 2 or more episodes of transient loss of consciousness (LOC) without clear medical explanation, or had a history of known or suspected pseudo seizure (psychogenic seizure). Patients with a history of seizure or epilepsy may have been eligible following discussion with the medical monitor.
• The patient required, or was likely to require, treatment with anticonvulsant medication during the study, or had taken anticonvulsant medication within 6 months before the screening visit.
• The patient had an unstable or uncontrolled medical (including illnesses related to the cardiovascular [including patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who had experienced the mitral valve prolapse syndrome], renal, or hepatic systems or surgical) condition (treated or untreated) or was not a suitable candidate for treatment with armodafinil, as judged by the investigator.
• The patient had neurosurgery involving the brain or brainstem.
• The patient had a history of schizophrenia, bipolar disorder, psychotic depression, or other psychotic episode.
• The patient had any current Axis I disorder (including depression and posttraumatic stress disorder [PTSD]), as assessed by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (SCID). The patient had any Axis II disorder (as assessed by SCID) that, in the opinion of the investigator, would affect patient participation in the study or full compliance with study procedures.
• The patient had a history of, or currently met The International Classification of Sleep Disorders, Edition 2 (ICSD 2) (American Academy of Sleep Medicine 2005) criteria for narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), shift work sleep disorder (SWSD), or any other sleep disorder associated with excessive daytime sleepiness; or the patient had a history of idiopathic hypersomnia, insomnia (requiring treatment), or sleep disorder before the development of the TBI.
• The patient had 85% or less sleep efficiency (sleep duration ÷ time in bed x 100%) as determined from nocturnal polysomnography (NPSG).
• The patient had any disorder that may interfere with drug absorption, distribution, metabolism, or excretion.
• The patient used any medications, including over-the-counter (OTC) medicines disallowed by the protocol, within 7 days or 5 half lives (medication or its active metabolites), whichever was longer, before the screening visit.
• The patient had a need for chronic pain medications.
• In the judgment of the investigator, the patient had a clinically significant deviation from normal in the physical examination.
• In the judgment of the investigator, the patient had any clinically significant ECG finding.
• The patient had a diagnosis of any type of dementia.
• The patient had a history of suicidal ideation (considered by the investigator to be of current clinical significance), or was currently suicidal.
• The patient had a known hypersensitivity to armodafinil, racemic modafinil, or any component of the study drug tablets. Armodafinil tablets contain the following inactive ingredients: croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch.
• The patient had a history of any clinically significant cutaneous drug reaction, or a history of clinically significant hypersensitivity reaction, including multiple allergies or drug reactions.
• The patient had a clinical laboratory test value(s) outside the range(s) specified by protocol (or any other clinically significant laboratory abnormality), and the medical monitor had not provided written approval for study participation.
• The patient had a history (within the past 5 years) of alcohol, narcotic, or any other drug abuse (with the exception of nicotine) as defined by the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, 4th Edition, Text Revision (DSM-IV-TR), or the patient had current evidence of substance use, without medical explanation, confirmed by results of a urine drug screen (UDS).
• The patient had taken armodafinil, modafinil or other stimulant medication for excessive sleepiness within 1 month of the screening visit.
• The patient was a pregnant or lactating woman. (Any women becoming pregnant during the study were to be withdrawn from the study.)
• The patient was known to have tested positive for human immunodeficiency virus (HIV).
• The patient consumed an average of more than 600 mg of caffeine per day, including coffee, tea and/or other caffeine-containing beverages or food.
• The patient used any investigational drug within 1 month before the screening visit.
• The patient was receiving workmen's compensation or was in active litigation with regard to TBI.
• The patient had a self-reported Hamilton Depression Rating Scale, 6 Item Version (S HAM D6) score of more than 4 at the screening visit.