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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Drug: Armodafinil
* Drug: Armodafinil
* Drug: Armodafinil
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Armodafinil 50 mg/day | Drug: Armodafinil<br>* Armodafinil 50 mg/day<br>|
| Experimental: 2<br>Armodafinil 150 mg/day | Drug: Armodafinil<br>* Armodafinil 150 mg/day<br>|
| Experimental: 3<br>Armodafinil 250 mg/day | Drug: Armodafinil<br>* Armodafinil 250 mg/day<br>|
| Placebo Comparator: 4<br>Placebo | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Multiple Sleep Latency Test (MSLT) at Endpoint (Last Postbaseline Observation Up to Week 12) | The MSLT is an objective assessment of sleepiness that measures the likelihood of falling asleep. Four 20-minute (maximum) MSLT naps were performed at 0900, 1100, 1300, and 1500. The participant, dressed in nonconstricting clothes, was instructed to lie quietly and attempt sleep. Each MSLT nap continued until: (a) 3 consecutive 30-second epochs of stage 1 sleep were reached or (b) any single, 30-second epoch of stage 2, 3, 4, or rapid eye movement (REM) sleep was reached. Sleep latency for each nap and average sleep latency for the 4 naps were tabulated. According to clinical protocol for the MSLT, each nap was terminated after 20 minutes if no sleep occurred. If a participant did not fall asleep in 20 minutes, his/her sleep latency for that nap was set to 20 minutes. Sleep latency was measured as the elapsed time from lights-out to the first epoch scored as sleep. With a 30-second scoring epoch, this criterion was reached when sleep occupied at least 16 seconds of any epoch. | Baseline, last postbaseline observation up to Week 12 | 
| Percentage of Responders and Nonresponders According to Clinical Global Impression of Change (CGI-C) Ratings at Endpoint (Last Postbaseline Observation Up to Week 12) | The CGI-C is the clinician's rating of disease severity as compared with pretreatment, assessed by the Clinical Global Impression of Severity (CGI-S). Severity of illness, as related to excessive sleepiness, was assessed at baseline by the CGI-S, which consists of 7 categories: normal-shows no sign of illness, borderline ill, mildly (slightly) ill, moderately ill, markedly ill, severely ill, and among the most extremely ill. The clinician assessed the change from baseline in the participant's condition, as related to excessive sleepiness, in response to treatment. The CGI-C uses the following 7 categories and scoring assignments: very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse. Responders were defined as those participants who were considered much or very much improved on the CGI-C. Those in all other categories of the CGI-C were considered nonresponders. | Last postbaseline observation up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Sleep Latency From the MSLT at Weeks 4, 8, and 12 | The MSLT is an objective assessment of sleepiness that measures the likelihood of falling asleep. Four 20-minute (maximum) MSLT naps were performed at 0900, 1100, 1300, and 1500. The participant, dressed in nonconstricting clothes, was instructed to lie quietly and attempt sleep. Each MSLT nap continued until: (a) 3 consecutive 30-second epochs of stage 1 sleep were reached or (b) any single, 30-second epoch of stage 2, 3, 4, or rapid eye movement (REM) sleep was reached. Sleep latency for each nap and average sleep latency for the 4 naps were tabulated. According to clinical protocol for the MSLT, each nap was terminated after 20 minutes if no sleep occurred. Sleep latency was measured as the elapsed time from lights-out to the first epoch scored as sleep. With a 30-second scoring epoch, this criterion was reached when sleep occupied at least 16 seconds of any epoch. | Baseline, Weeks 4, 8, and 12 | 
| Percentage of Responders and Nonresponders According to Clinical Global Impression of Change (CGI-C) Ratings at Weeks 2, 4, 8, and 12 | The CGI-C is the clinician's rating of disease severity as compared with pretreatment, assessed by the Clinical Global Impression of Severity (CGI-S). Severity of illness, as related to excessive sleepiness, was assessed at baseline by the CGI-S, which consists of 7 categories: normal-shows no sign of illness, borderline ill, mildly (slightly) ill, moderately ill, markedly ill, severely ill, and among the most extremely ill. The clinician assessed the change from baseline in the participant's condition, as related to excessive sleepiness, in response to treatment. The CGI-C uses the following 7 categories and scoring assignments: very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse. Responders were defined as those participants who were considered much or very much improved on the CGI-C. Those in all other categories of the CGI-C were considered nonresponders. | Weeks 2, 4, 8, and 12 | 
| Change From Baseline in Traumatic Brain Injury - Work Instability Scale (TBI-WIS) Total Score At Weeks 4, 8, 12 and Endpoint (Last Postbaseline Observation Up to Week 12) | The TBI-WIS is a validated participant-rated instrument for assessing a participant's functional ability after TBI and the functional demands of their job. The assessment consists of 36 questions to which the participant responded with a true or not true answer. To score the questionnaire, the number of true responses is counted: if < 2, the risk is low; 2 to 23, the risk is medium; and >23, the risk is high, for work instability. Score range is 0 (lowest risk for work instability) to 36 (highest risk for work instability). | Weeks 4, 8, 12 and Endpoint (last postbaseline observation up to Week 12) | 
| Change From Baseline in Epworth Sleepiness Scale (ESS) at Week 12 and Endpoint (Last Postbaseline Observation Up to Week 12) | The patient's evaluation of excessive daytime sleepiness was measured by the ESS. The ESS score is based on responses to questions referring to 8 everyday situations (eg, sitting and reading, talking to someone, being stopped in traffic) and reflects a patient's propensity to fall asleep in those situations. The ESS score is derived from the sum of the values from questions corresponding to the 8 situations. Scores for the ESS range from 0 to 24, with a higher score indicating a greater daytime sleepiness. This test was self-administered. | Baseline, Week 12, Endpoint (last postbaseline observation, up to Week 12) | 
| Percentage of Participants Answering No to All Questions on the Columbia-Suicide Severity Rating Scale Since Last Visit Version (C-SSRS SLV) at Weeks 2, 4, 8, 12 and Endpoint (Last Postbaseline Observation Up to Week 12) | The C-SSRS captures occurrence, severity, and frequency of suicide-related thoughts and behaviors since last visit (SLV). The number of participants answering 'no' to all 9 yes/no questions about suicidal behaviors, ideations, and acts are presented. Questions included the presence of the following: a wish to be dead; nonspecific active suicidal thoughts; actual suicide attempt; non-suicidal self-injurious behavior; interrupted attempt; aborted attempt; suicidal behavior; preparatory suicidal acts or behavior; and completed suicide. | Weeks 4, 8, 12 and Endpoint (last postbaseline observation up to Week 12) | 
| Change From Baseline in the Total Score From the Self-Reported Hamilton Depression Rating Scale, 6 Item Version (S-HAM-D6) at Weeks 2, 4, 8, 12 and Endpoint (Last Postbaseline Observation Up to 12 Weeks) | The self-reported S-HAM-D6 is a validated scale developed from the core depressive items of the 17 Item Hamilton Depression Inventory (HAM-D17). The HAM-D6 (Items 1, 2, 7, 8, 10, 13 from the 17-item HAMD) evaluates core symptoms of Major Depressive Disorder (MDD). The assessment consists of 6 items representing depressed mood, guilt, work and activities, retardation, psychic anxiety, and general somatic symptoms. Each item is evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). Total scores range from 0 (normal) to 22 (severe). Scores greater than 12 indicate moderate to severe depression and scores less than 12 indicate mild depression. | Baseline, Weeks 2, 4, 8, 12, and Endpoint (last postbaseline observation up to 12 weeks) | 
| Change From Baseline in the Total Sleep Time As Assessed by Nocturnal Polysomnography (NPSG) at Weeks 2, 4, 12 and Endpoint (Last Postbaseline Observation Up to 12 Weeks) | NPSG continuously records normal and abnormal physiological activity during an entire night. It documents the adequacy of sleep, including the frequency, duration, and total amounts of stage 1-2, stage 3-4 (slow wave sleep), and rapid eye movement (REM) sleep. | Baseline, Weeks 2, 4, 12, and Endpoint (last postbaseline observation up to 12 weeks) | 
| Plasma Concentrations of Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) at Weeks 4, 8, and 12 (or Last Postbaseline Observation Up to Week 12) | To evaluate the impact of treatment with armodafinil on the pharmacokinetics of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) (as appropriate), plasma concentrations at weeks 4, 8, and 12 (or last postbaseline observation) were to be assessed. | Weeks 4, 8, and 12 (or last postbaseline observation, up to Week 12) | 
| Concomitant Medication Usage In ≥5% of Participants Throughout the Study | Therapeutic classification of concomitant medications used by ≥5% of participants throughout the study. Participants are counted only once in each therapeutic class category. Medications were included in the table if the proportion of participants in the combined armodafinil treatment group was ≥5%. | Screening through Week 12 | 
| Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Withdrawals Due to AEs | AE=any untoward medical occurrence in a patient that develops or worsens in severity during the conduct of the clinical study of a pharmaceutical product and does not necessarily have a causal relationship to the study drug. SAE=any AE that resulted in any of the following: death; a life-threatening adverse event; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; a congenital anomaly or birth defect; an important medical event that required medical intervention to prevent 1 of the outcomes listed in this definition. Treatment-related AEs=definite, probable, possible, or missing relationship. Protocol-defined AEs=treatment-emergent adverse events associated with skin rash, hypersensitivity reaction, emergent suicidal ideation or suicide attempt, depression, psychosis (including hypomanic or manic episode), and seizure or suspected seizure were considered to be of potential clinical importance. | Screening through Week 12 | 
| Number of Participants With Clinically Significant Abnormal Postbaseline Serum Chemistry Values | Normal ranges for serum chemistry values: blood urea nitrogen (BUN), 1.43 - 8.57 mmol/L; uric acid, 124.91 - 493.68 μmol/L; aspartate aminotransferase (AST), 11 - 36 U/L; gamma-glutamyl transpeptidase (GGT), 10 - 61 U/L; total bilirubin, 3.42 - 20.52 μmol/L. | Baseline, last postbaseline observation up to Week 12 | 
| Number of Participants With Clinically Significant Abnormal Postbaseline Hematology Values | Normal ranges for hematology values: white blood cell (WBC) count, 3.8 - 10.7 x 10^9/L; absolute neutrophil count (ANC), 1.96 - 7.23 x 10^9/L. Participants may have had more than one clinically significant abnormal value. | Baseline, last postbaseline observation up to Week 12 | 
| Number of Participants With Clinically Significant Abnormal Postbaseline Urinalysis Values | Participants with at least one clinically significant postbaseline urinalysis abnormality, specifically presented is blood (hemoglobin) in urine >=2 units increase from baseline. | Baseline, last postbaseline observation up to Week 12 | 
| Number of Participants With Clinically Significant Abnormal Vital Sign Values | Criteria for clinically significant abnormal vital signs values: heart rate, ≤50 beats per minute (bpm) and decrease from baseline of ≥15 bpm; sitting systolic blood pressure, ≤90 mm Hg and decrease from baseline of ≥20 mm Hg; sitting diastolic blood pressure, ≤50 mm Hg and decrease from baseline of ≥15 mm Hg. | Baseline, last postbaseline observation up to Week 12 | 
| Number of Participants With Notable Blood Pressure Values Per World Health Organization Criteria | Criteria for World Health Organization (WHO) notable blood pressure (BP) values: systolic blood pressure, ≥140 mm Hg plus increase of ≥10% from baseline; diastolic blood pressure, ≥90 mm Hg plus increase of ≥10% from baseline. | Baseline, last postbaseline observation up to Week 12 | 
| Electrocardiogram (ECG) Findings Shifts From Baseline to Overall | Number of participants with shifts from normal/abnormal 12-lead ECG findings at baseline (BL) to (→) normal/abnormal findings overall are presented. For overall, the worst postbaseline finding (the abnormal finding if there are both normal and abnormal findings) for the participant between baseline and endpoint (defined as last postbaseline observation, up to Week 12) is summarized. Shifts (normal and abnormal) from baseline to overall are summarized using participant counts. Any ECG finding that was judged by the investigator as a clinically meaningful change (worsening) compared to baseline was recorded as an adverse event. | Baseline through Endpoint (last postbaseline observation, up to Week 12) | 
| Physical Examination Findings Shifts From Baseline to Endpoint (Last Postbaseline Observation, up to Week 12) | Number of participants with shifts from normal/abnormal physical examination findings at baseline (BL) to (→) normal/abnormal findings at endpoint (EP, defined as last postbaseline observation, up to Week 12). Shifts (normal and abnormal) from baseline to endpoint are summarized using participant counts for each physical examination category. A newly diagnosed finding was defined as being normal or missing at baseline and abnormal at least once during the study. Any physical examination finding that was judged by the investigator as a clinically significant change (worsening) compared to a baseline value was considered an adverse event. HEENT=head, eyes, ears, nose, throat. | Baseline through Endpoint (last postbaseline observation, up to Week 12) |