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

A 12-Month, Open-Label Study to Evaluate the Safety, Tolerability, and Efficacy of Armodafinil (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 this study is to evaluate the safety and tolerability of long-term (12 months) armodafinil treatment in patients with excessive sleepiness associated with mild or moderate closed traumatic brain injury (TBI).

Patients enrolled in this study will be rollover patients (those who completed the previous double-blind efficacy study C10953/3067/ES/MN) and new patients (those who did not participate in the C10953/3067/ES/MN study).

Inclusion Criteria (for New Patients):

• The patient has a mild (Glasgow Coma Scale [GCS] score = 13-15) or moderate (GCS score = 9-12) closed traumatic brain injury (TBI) at the time of the injury, and the injury occurred 1 to 10 years prior to screening.
• The patient has a Glasgow Outcome Scale score of 5.
• The patient has an Epworth Sleepiness Scale (ESS) score of at least 10.
• The patient has a mean sleep latency on the Multiple Sleep Latency Test (MSLT) (average of 4 naps) of less than 8 minutes.
• The patient has a Clinical Global Impression of Severity of Illness (CGI-S) rating relating to their excessive sleepiness of 4 or more.
• The patient has 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 identified according to the first inclusion criterion.
• Written informed consent was obtained.
• If admitted to an in-patient treatment facility, the patient was discharged at least 1 month prior to the screening visit.
• The patient does 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 1 of those methods for the duration of the study (and for 30 days after participation in the study).
• The patient is 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 is willing and able to comply with study restrictions and attend regularly scheduled clinic visits as specified in the protocol.
• The patient has an 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 inhibitor [SSRIs] and serotonin and norepinephrine reuptake inhibitor [SNRIs]), 8 weeks (contraceptives), or 4 weeks (all other allowed medication) before the screening visit and is not likely to require a change in therapy for at least 12 weeks on the basis of the investigators' assessment.
• The patient has 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 has no other head injury fulfilling the criteria for TBI within ±1 year of the TBI identified according to the first inclusion criterion.
• The patient has a habitual bedtime between 2100 and 2400.

Inclusion Criteria (for Rollover Patients from Study C10953/3067/ES/MN):

• The patient has completed 12 weeks of double-blind treatment in Study C10953/3067/ES/MN.
• Written informed consent was obtained.
• Women of childbearing potential (not surgically sterile or 2 years postmenopausal), used a medically accepted method of contraception and agreed to continue use 1 of those methods for the duration of the study and for 30 days after participation in the study.
• The patient is in otherwise good health, as judged by the investigator, on the basis of a medical and psychiatric history, physical examination, ECG, serum chemistry, hematology, and urinalysis.
• The patient is willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period, and was willing to return to the clinic for the follow-up evaluation as specified in the protocol.

Exclusion Criteria (for New Patients):

• The patient has a history of 2 or more episodes of transient loss of consciousness without clear medical explanation, or has a history of known or suspected pseudo seizure (psychogenic seizure). Patients with a history of seizure or epilepsy may be eligible following discussion with the medical monitor.
• The patient requires, or is likely to require, treatment with anticonvulsant medication during the study; or has taken anticonvulsant medication within 6 months before the screening visit.
• The patient has an unstable or uncontrolled medical (including illnesses related to the cardiovascular, 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 has had neurosurgery involving the brain or brainstem.
• The patient has a history of schizophrenia, bipolar disorder, psychotic depression, or other psychotic episode.
• The patient has 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). Patients with any Axis II disorder, that in the opinion of the investigator, would affect patient participation in the study or full compliance with study procedures.
• The patient has a history of, or currently meets The International Classification of Sleep Disorders, Edition 2 (ICSD-2) criteria for any other sleep disorder associated with excessive daytime sleepiness; or the patient has a history of idiopathic hypersomnia, insomnia (requiring treatment), or sleep disorder before the development of the TBI.
• The patient has 85% or less sleep efficiency (sleep duration ÷ time in bed x 100%) as determined from Nocturnal Polysomnography (NPSG).
• The patient has any disorder that may have interfered with drug absorption, distribution, metabolism, or excretion.
• The patient has 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 is longer.
• The patient has a need for chronic pain medications.
• In the judgment of the investigator, the patient has a clinically significant deviation from normal in the physical examination.
• In the judgment of the investigator, the patient has any clinically significant ECG finding.
• The patient has a diagnosis of any type of dementia.
• The patient has a history of suicidal ideation (considered by the investigator to be of clinical significance), or is suicidal.
• The patient has a known hypersensitivity to armodafinil, racemic modafinil, or any component of the study drug tablets. Armodafinil tablets contained the following inactive ingredients: croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch.
• The patient has 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 has a clinical laboratory test value(s) outside the range(s) specified in the protocol (or any other clinically significant laboratory abnormality), and the medical monitor had not provided written approval for study participation.
• The subject has 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 (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 has taken armodafinil, modafinil, or other stimulant medication for excessive sleepiness within 1 month of the screening visit.
• The patient is a pregnant or lactating woman.
• The patient is known to have tested positive for human immunodeficiency virus (HIV).
• The patient consumes an average of more than 600 mg of caffeine per day, including coffee, tea and/or other caffeine-containing beverages or food.
• The patient has used any investigational drug within 1 month before the screening visit.
• The patient is receiving workmen's compensation or was in active litigation with regard to TBI.
• The patient has a Self-Reported Hamilton Depression Rating Scale, 6 Item Version (S-HAM-D6) score of more than 4.

Exclusion Criteria (for Rollover Patients from Study C10953/3067/ES/MN):

• The patient has any clinically significant unstable or uncontrolled medical, surgical, or psychiatric conditions (treated or untreated) or may not be a suitable candidate for treatment with armodafinil, as judged by the investigator or medical monitor.
• The patient has current evidence of active psychosis, including stimulant-induced psychosis or mania.
• The patient has current evidence of non-medical substance use confirmed by results of a UDS.
• The patient has used any medications including OTC medicines disallowed by the protocol (except armodafinil use in study 3067) within 7 days or 5 half-lives of the drug and its active metabolites, whichever is longer.
• The patient has a clinically significant deviation from normal in the physical examination as judged by the investigator.
• The patient has a clinically significant laboratory abnormality, as judged by the investigator, without prior written approval by the medical monitor.
• The patient has hypersensitivity to armodafinil or modafinil, or any of the excipients of either.
• The patient is a pregnant or lactating woman.
• The patient is unlikely to comply with the study protocol, or is unsuitable for any other reason, as judged by the investigator.
• The patient consumes an average of more than 600 mg of caffeine per day (approximately equivalent to 5 or more cups of coffee), including coffee, tea, and/or other caffeine-containing beverages or food.