Clinical trial NCT00893789: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Traumatic Brain Injury
Lead sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor class: INDUSTRY
First posted: 2009-05-06
Enrollment: 117
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in Multiple Sleep Latency Test (MSLT) at Endpoint (Last Postbaseline Observation Up to Week 12)
timeFrame: Baseline, last postbaseline observation up to Week 12
measure: Percentage of Responders and Nonresponders According to Clinical Global Impression of Change (CGI-C) Ratings at Endpoint (Last Postbaseline Observation Up to Week 12)
timeFrame: Last postbaseline observation up to Week 12
Secondary outcomes:
measure: Change From Baseline in Mean Sleep Latency From the MSLT at Weeks 4, 8, and 12
timeFrame: Baseline, Weeks 4, 8, and 12
measure: Percentage of Responders and Nonresponders According to Clinical Global Impression of Change (CGI-C) Ratings at Weeks 2, 4, 8, and 12
timeFrame: Weeks 2, 4, 8, and 12
measure: 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)
timeFrame: Weeks 4, 8, 12 and Endpoint (last postbaseline observation up to Week 12)
measure: Change From Baseline in Epworth Sleepiness Scale (ESS) at Week 12 and Endpoint (Last Postbaseline Observation Up to Week 12)
timeFrame: Baseline, Week 12, Endpoint (last postbaseline observation, up to Week 12)
measure: 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)
timeFrame: Weeks 4, 8, 12 and Endpoint (last postbaseline observation up to Week 12)
measure: 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)
timeFrame: Baseline, Weeks 2, 4, 8, 12, and Endpoint (last postbaseline observation up to 12 weeks)
measure: 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)
timeFrame: Baseline, Weeks 2, 4, 12, and Endpoint (last postbaseline observation up to 12 weeks)
measure: 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)
timeFrame: Weeks 4, 8, and 12 (or last postbaseline observation, up to Week 12)
measure: Concomitant Medication Usage In ≥5% of Participants Throughout the Study
timeFrame: Screening through Week 12
measure: Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Withdrawals Due to AEs
timeFrame: Screening through Week 12
measure: Number of Participants With Clinically Significant Abnormal Postbaseline Serum Chemistry Values
timeFrame: Baseline, last postbaseline observation up to Week 12
measure: Number of Participants With Clinically Significant Abnormal Postbaseline Hematology Values
timeFrame: Baseline, last postbaseline observation up to Week 12
measure: Number of Participants With Clinically Significant Abnormal Postbaseline Urinalysis Values
timeFrame: Baseline, last postbaseline observation up to Week 12
measure: Number of Participants With Clinically Significant Abnormal Vital Sign Values
timeFrame: Baseline, last postbaseline observation up to Week 12
measure: Number of Participants With Notable Blood Pressure Values Per World Health Organization Criteria
timeFrame: Baseline, last postbaseline observation up to Week 12
measure: Electrocardiogram (ECG) Findings Shifts From Baseline to Overall
timeFrame: Baseline through Endpoint (last postbaseline observation, up to Week 12)
measure: Physical Examination Findings Shifts From Baseline to Endpoint (Last Postbaseline Observation, up to Week 12)
timeFrame: Baseline through Endpoint (last postbaseline observation, up to Week 12)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Teva Investigational Site 58
state: Alabama
city: Tucson
country: United States
facility: Teva Investigational Site 62
state: Arizona
city: Tucson
country: United States
facility: Teva Investigational Site 40
state: Arizona
city: Hot Springs
country: United States
facility: Teva Investigational Site 16
state: Arkansas
city: Little Rock
country: United States
facility: Teva Investigational Site 5
state: Arkansas
city: Fountain Valley
country: United States
facility: Teva Investigational Site 44
state: California
city: La Palma
country: United States
facility: Teva Investigational Site 49
state: California
city: La Palma
country: United States
facility: Teva Investigational Site 51
state: California
city: Mather
country: United States
facility: Teva Investigational Site 71
state: California
city: San Diego
country: United States
facility: Teva Investigational Site 55
state: California
city: San Diego
country: United States
facility: Teva Investigational Site 33
state: California
city: Santa Monica
country: United States
facility: Teva Investigational Site 53
state: California
city: Wallingford
country: United States
facility: Teva Investigational Site 69
state: Connecticut
city: Hallandale Beach
country: United States
facility: Teva Investigational Site 52
state: Florida
city: Miami
country: United States
facility: Teva Investigational Site 47
state: Florida
city: Orlando
country: United States
facility: Teva Investigational Site 1
state: Florida
city: Pembroke Pines
country: United States
facility: Teva Investigational Site 18
state: Florida
city: Saint Petersburg
country: United States
facility: Teva Investigational Site 38
state: Florida
city: Spring Hill
country: United States
facility: Teva Investigational Site 10
state: Florida
city: Tampa
country: United States
facility: Teva Investigational Site 17
state: Florida
city: Atlanta
country: United States
facility: Teva Investigational Site 26
state: Georgia
city: Atlanta
country: United States
facility: Teva Investigational Site 12
state: Georgia
city: Atlanta
country: United States
facility: Teva Investigational Site 14
state: Georgia
city: Gainesville
country: United States
facility: Teva Investigational Site 68
state: Georgia
city: Macon
country: United States
facility: Teva Investigational Site 67
state: Georgia
city: Stockbridge
country: United States
facility: Teva Investigational Site 29
state: Georgia
city: Suwanee
country: United States
facility: Teva Investigational Site 15
state: Georgia
city: Chicago
country: United States
facility: Teva Investigational Site 46
state: Illinois
city: Chicago
country: United States
facility: Teva Investigational Site 54
state: Illinois
city: Chicago
country: United States
facility: Teva Investigational Site 59
state: Illinois
city: Danville
country: United States
facility: Teva Investigational Site 28
state: Indiana
city: Fort Wayne
country: United States
facility: Teva Investigational Site 19
state: Indiana
city: Indianapolis
country: United States
facility: Teva Investigational Site 2
state: Indiana
city: Indianapolis
country: United States
facility: Teva Investigational Site 39
state: Indiana
city: Iowa City
country: United States
facility: Teva Investigational Site 41
state: Iowa
city: Shawnee Mission
country: United States
facility: Teva Investigational Site 9
state: Kansas
city: Louisville
country: United States
facility: Teva Investigational Site 48
state: Kentucky
city: Chevy Chase
country: United States
facility: Teva Investigational Site 32
state: Maryland
city: Belmont
country: United States
facility: Teva Investigational Site 37
state: Massachusetts
city: Brighton
country: United States
facility: Teva Investigational Site 70
state: Massachusetts
city: Saginaw
country: United States
facility: Teva Investigational Site 22
state: Michigan
city: Hattiesburg
country: United States
facility: Teva Investigational Site 7
state: Mississippi
city: Saint Louis
country: United States
facility: Teva Investigational Site 42
state: Missouri
city: Lincoln
country: United States
facility: Teva Investigational Site 56
state: Nebraska
city: New York
country: United States
facility: Teva Investigational Site 72
state: New York
city: New York
country: United States
facility: Teva Investigational Site 63
state: New York
city: West Seneca
country: United States
facility: Teva Investigational Site 36
state: New York
city: Durham
country: United States
facility: Teva Investigational Site 11
state: North Carolina
city: Winston-Salem
country: United States
facility: Teva Investigational Site 45
state: North Carolina
city: Cincinnati
country: United States
facility: Teva Investigational Site 31
state: Ohio
city: Cincinnati
country: United States
facility: Teva Investigational Site 34
state: Ohio
city: Middleburg Heights
country: United States
facility: Teva Investigational Site 57
state: Ohio
city: Toledo
country: United States
facility: Teva Investigational Site 30
state: Ohio
city: Oklahoma City
country: United States
facility: Teva Investigational Site 3
state: Oklahoma
city: Clarks Summit
country: United States
facility: Teva Investigational Site 64
state: Pennsylvania
city: Jefferson Hills
country: United States
facility: Teva Investigational Site 13
state: Pennsylvania
city: Columbia
country: United States
facility: Teva Investigational Site 65
state: South Carolina
city: Germantown
country: United States
facility: Teva Investigational Site 61
state: Tennessee
city: Austin
country: United States
facility: Teva Investigational Site 60
state: Texas
city: Dallas
country: United States
facility: Teva Investigational Site 25
state: Texas
city: Houston
country: United States
facility: Teva Investigational Site 8
state: Texas
city: Houston
country: United States
facility: Teva Investigational Site 20
state: Texas
city: Kingwood
country: United States
facility: Teva Investigational Site 73
state: Texas
city: San Antonio
country: United States
facility: Teva Investigational Site 23
state: Texas
city: Midvale
country: United States
facility: Teva Investigational Site 35
state: Utah
city: Midvale
country: United States
facility: Teva Investigational Site 66
state: Utah
city: Richmond
country: United States
facility: Teva Investigational Site 24
state: Virginia
city: West Allis
country: United States
facility: Teva Investigational Site 50
state: Wisconsin
city: Berlin
country: Germany
facility: Teva Investigational Site 405
city: Munchen
country: Germany
facility: Teva Investigational Site 404
city: Pisa
country: Italy
facility: Teva Investigational Site 501
city: Barcelona
country: Spain
facility: Teva Investigational Site 704
city: Madrid
country: Spain
facility: Teva Investigational Site 701
Study officials:
affiliation: Teva Branded Pharmaceutical Products R&D, Inc.
name: Sponsor's Medical Expert, MD
role: STUDY_DIRECTOR
References:
citation: Menn SJ, Yang R, Lankford A. 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. J Clin Sleep Med. 2014 Nov 15;10(11):1181-91. doi: 10.5664/jcsm.4196.