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

NCT00983437 | Terminated Phase 3 Results

• 1 other identifier: C10953/3069/ES/MN
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 61

Brief Summary

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).

Conditions

Traumatic Brain Injury

Outcome Measures

Primary Outcomes (11)

• Safety and Tolerability: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths and Discontinuations Due to AEs

  AE=any untoward medical occurrence 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 to study drug. Protocol-defined AEs=treatment-emergent adverse events associated with skin rash, hypersensitivity reaction, emergent suicidal ideation or suicide attempt, depression, psychosis, and seizure or suspected seizure were considered to be of potential clinical importance. DB=double-blind portion of the study (NCT00893789).

  Assessed from Screening through end of treatment; median (full range) of treatment was 98 (5.0 to 326.0) days.

• Safety and Tolerability: Concomitant Medication Usage In Participants Throughout the Study

  Therapeutic classification of concomitant medications used by participants throughout the study. Participants are counted only once in each therapeutic class category.

  Assessed from Screening through end of treatment; median (full range) of treatment was 98 (5.0 to 326.0) days.

• Safety and Tolerability: Number of Participants With Clinically Significant Serum Chemistry Test Results

  Criteria for clinically significant abnormal serum chemistry values: alanine aminotransferase (ALT) ≥3x upper limit of normal (ULN); aspartate aminotransferase (AST) ≥3x ULN; alkaline phosphatase ≥3x ULN; gamma-glutamyl transpeptidase (GGT) ≥3x ULN; lactate dehydrogenase (LDH) ≥3x ULN; blood urea nitrogen (BUN) ≥10.71 mmol/L; creatinine ≥177 μmol/L; uric acid, men ≥625 μmol/L, women ≥506 μmol/L; bilirubin (total) ≥34.2 μmol/L.

  Assessed at Screening, Months 6 and 12 (or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Safety and Tolerability: Number of Participants With Clinically Significant Abnormal Vital Signs Measurements

  Criteria for clinically significant abnormal vital signs values: pulse, ≥120 beats per minute (bpm) and increase from baseline of ≥15 bpm or ≤50 bpm and decrease from baseline of ≥15 bpm; systolic blood pressure, ≥180 mm Hg and increase from baseline of ≥20 mm Hg or ≤90 mm Hg and decrease from baseline of ≥20 mm Hg; diastolic blood pressure, ≥105 mm Hg and increase from baseline of ≥15 mm Hg or ≤50 mm Hg and decrease from baseline of ≥15 mm Hg; temperature \>38.3º celsius (C) and change from baseline of ≥1.1°C. Baseline was defined as the baseline value from the double-blind study C10953/3067/ES/MN (NCT00893789) from which the participants entered into this open-label study.

  Baseline, Week 2, Months 1, 2, 3, 6, 9, and 12 (or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Safety and Tolerability: Number of Participants With Clinically Significant Abnormal Hematology Test Results

  Criteria for clinically significant abnormal hematology values: hematocrit, men \<0.37 L/L or women \<0.32 L/L; hemoglobin, men ≤115 g/L or women ≤95 g/L; white blood cell (WBC) count ≤3x10\^9/L or ≥20x10\^9/L; eosinophils ≥10%; absolute neutrophil count (ANC) ≤1x10\^9/L; platelet count ≤75x10\^9/L or ≥700x10\^9/L.

  Assessed at Screening, Months 6 and 12 (or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Safety and Tolerability: Number of Participants With Clinically Significant Abnormal Urinalysis Results

  Criteria for clinically significant abnormal urinalysis values: blood (hemoglobin) ≥2 unit increase from baseline; glucose ≥2 unit increase from baseline; ketones ≥2 unit increase from baseline; total protein ≥2 unit increase from baseline. Baseline was defined as the baseline value from the double-blind study C10953/3067/ES/MN (NCT00893789) from which the participants entered into this open-label study.

  Baseline, Months 6 and 12 (or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Safety and Tolerability: 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 was defined as the baseline value from the double-blind study C10953/3067/ES/MN (NCT00893789) from which the participants entered into this open-label study.

  Baseline, Week 2, Months 1, 2, 3, 6, 9, and 12 (or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Safety and Tolerability: 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. 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 was defined as the baseline value from the double-blind study C10953/3067/ES/MN (NCT00893789) from which the participants entered into this open-label study.

  Baseline through Endpoint (Month 12 or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Safety and Tolerability: Physical Examination Findings Shifts From Baseline to Endpoint (Month 12 or Last Postbaseline Observation)

  Number of participants with shifts from normal/abnormal physical examination findings at baseline (BL) to (→) normal/abnormal findings at endpoint (EP). 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 was defined as the baseline value from the double-blind study C10953/3067/ES/MN (NCT00893789) from which the participants entered into this open-label study.

  Baseline through Endpoint (Month 12 or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Number of Participants Answering "Yes" to Any Question on the Columbia-Suicide Severity Rating Scale Since Last Visit Version (C-SSRS SLV) at Week 2, Months 1, 2, 3, 6, 9, and Endpoint (Month 12, or Last Postbaseline Observation)

  The percentage of participants answering 'yes' to any of the 9 yes/no questions about suicidal behaviors, ideations, and acts at given time points are presented. The C-SSRS captures occurrence, severity, and frequency of suicide-related thoughts and behaviors since last visit (SLV). Questions included the presence (yes) or absence (no) 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.

  Week 2, Months 1, 2, 3, 6, 9, and Endpoint (Month 12, or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Change From Baseline in the Total Score From the Self-Reported Hamilton Depression Rating Scale, 6 Item Version (S-HAM-D6) at Week 2, Months 1, 2, 3, 6, 9, and Endpoint (Month 12, or Last Postbaseline Observation)

  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. Baseline was defined as the baseline value from the double-blind study C10953/3067/ES/MN (NCT00893789) from which the participants entered into this open-label study.

  Baseline, Week 2, Months 1, 2, 3, 6, 9, and Endpoint (Month 12, or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

Secondary Outcomes (5)

• Change From Baseline in Epworth Sleepiness Scale (ESS) at Week 2 and Months 1, 2, 3, 6, 9, and Endpoint (Month 12 or Last Postbaseline Observation)

  Baseline, Week 2 and Months 1, 2, 3, 6, 9, and Endpoint (Month 12 or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Change From Baseline in Clinical Global Impression of Severity of Illness (CGI-S) at Week 2 and Months 1, 2, 3, 6, 9, and Endpoint (Month 12 or Last Postbaseline Observation)

  Baseline, Week 2 and Months 1, 2, 3, 6, 9, and Endpoint (Month 12 or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Percentage of Participants With Improvement on the Clinical Global Impression of Severity of Illness (CGI-S) at Week 2 and Months 1, 2, 3, 6, 9, and Endpoint (Month 12 or Last Postbaseline Observation)

  Week 2 and Months 1, 2, 3, 6, 9, and Endpoint (Month 12 or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Change From Baseline in Traumatic Brain Injury - Work Instability Scale (TBI-WIS) Score Values at Months 3, 6, 9, and Endpoint (Month 12 or Last Postbaseline Observation)

  Baseline, Months 3, 6, 9, and Endpoint (Month 12 or last postbaseline observation); median (full range) of treatment was 98 (5.0 to 326.0) days.

• Change From Baseline in the Medical Outcomes Study 6-Item Cognitive Functioning Scale (MOS-CF6) Total Score at Months 3, 6, 9, and Endpoint (Month 12 or Last Postbaseline Observation)

  Baseline, Months 3, 6, 9, and 12 (or last postbaseline observation)

Study Arms (1)

Armodafinil

EXPERIMENTAL

Armodafinil tablets 150 mg or 250 mg administered orally, once daily in the morning.

Drug: Armodafinil

Interventions

Armodafinil DRUG

Also known as: CEP-10953

Armodafinil

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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 a habitual bedtime between 2100 and 2400.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Cephalon, Inc.: lead

Study Sites (61)

Teva Investigational Site 58

Birmingham, Alabama, 35213, United States

Location

Teva Investigational Site 62

Tucson, Arizona, 85712, United States

Location

Teva Investigational Site 16

Hot Springs, Arkansas, 71913, United States

Location

Teva Investigational Site 5

Little Rock, Arkansas, 72205, United States

Location

Teva Investigational Site 44

Fountain Valley, California, 92708, United States

Location

Teva Investigational Site 49

La Palma, California, 90623, United States

Location

Teva Investigational Site 51

La Palma, California, 90623, United States

Location

Teva Investigational Site 55

San Diego, California, 92103, United States

Location

Teva Investigational Site 33

San Diego, California, 92161, United States

Location

Teva Investigational Site 53

Santa Monica, California, 90404, United States

Location

Teva Investigational Site 69

Wallingford, Connecticut, 06492, United States

Location

Teva Investigational Site 52

Hallandale, Florida, 33009, United States

Location

Teva Investigational Site 47

Miami, Florida, 33173, United States

Location

Teva Investigational Site 1

Orlando, Florida, 32806, United States

Location

Teva Investigational Site 18

Pembroke Pines, Florida, 33026, United States

Location

Teva Investigational Site 10

Spring Hill, Florida, 34609, United States

Location

Teva Investigational Site 38

St. Petersburg, Florida, 33707, United States

Location

Teva Investigational Site 17

Tampa, Florida, 33607, United States

Location

Teva Investigational Site 12

Atlanta, Georgia, 30342, United States

Location

Teva Investigational Site 14

Atlanta, Georgia, 30342, United States

Location

Teva Investigational Site 68

Gainesville, Georgia, 30501, United States

Location

Teva Investigational Site 67

Macon, Georgia, 31201, United States

Location

Teva Investigational Site 15

Suwanee, Georgia, 30024, United States

Location

Teva Investigational Site 46

Chicago, Illinois, 60675-6714, United States

Location

Teva Investigational Site 54

Chicago, Illinois, 60675-6714, United States

Location

Teva Investigational Site 59

Chicago, Illinois, 60675-6714, United States

Location

Teva Investigational Site 28

Danville, Indiana, 46122, United States

Location

Teva Investigational Site 19

Fort Wayne, Indiana, 46805, United States

Location

Teva Investigational Site 2

Indianapolis, Indiana, 46250, United States

Location

Teva Investigational Site 39

Indianapolis, Indiana, 46260, United States

Location

Teva Investigational Site 41

Iowa City, Iowa, 52242, United States

Location

Teva Investigational Site 9

Shawnee Mission, Kansas, 66201, United States

Location

Teva Investigational Site 48

Louisville, Kentucky, 40217, United States

Location

Teva Investigational Site 32

Chevy Chase, Maryland, 20815-6901, United States

Location

Teva Investigational Site 37

Belmont, Massachusetts, 02478, United States

Location

Teva Investigational Site 22

Saginaw, Michigan, 48604, United States

Location

Teva Investigational Site 7

Hattiesburg, Mississippi, 39402, United States

Location

Teva Investigational Site 42

St Louis, Missouri, 63143, United States

Location

Teva Investigational Site 56

Lincoln, Nebraska, 68510, United States

Location

Teva Investigational Site 63

New York, New York, 10019, United States

Location

Teva Investigational Site 36

West Seneca, New York, 14224, United States

Location

Teva Investigational Site 11

Durham, North Carolina, 27710, United States

Location

Teva Investigational Site 45

Winston-Salem, North Carolina, 27157, United States

Location

Teva Investigational Site 31

Cincinnati, Ohio, 45227, United States

Location

Teva Investigational Site 34

Cincinnati, Ohio, 45246, United States

Location

Teva Investigational Site 57

Middleburg Heights, Ohio, 44130, United States

Location

Teva Investigational Site 30

Toledo, Ohio, 43623, United States

Location

Teva Investigational Site 3

Oklahoma City, Oklahoma, 73112, United States

Location

Teva Investigational Site 64

Clarks Summit, Pennsylvania, 18411, United States

Location

Teva Investigational Site 13

Jefferson Hills, Pennsylvania, 15025, United States

Location

Teva Investigational Site 65

Columbia, South Carolina, 29201, United States

Location

Teva Investigational Site 61

Germantown, Tennessee, 38139, United States

Location

Teva Investigational Site 60

Austin, Texas, 78756, United States

Location

Teva Investigational Site 25

Dallas, Texas, 75235, United States

Location

Teva Investigational Site 8

Houston, Texas, 77030, United States

Location

Teva Investigational Site 20

Houston, Texas, 77063, United States

Location

Teva Investigational Site 23

San Antonio, Texas, 78229, United States

Location

Teva Investigational Site 35

Midvale, Utah, 84047, United States

Location

Teva Investigational Site 66

Midvale, Utah, 84047, United States

Location

Teva Investigational Site 24

Richmond, Virginia, 23249, United States

Location

Teva Investigational Site 50

West Allis, Wisconsin, 53227, United States

Location

Related Publications (1)

• 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.

  PMID: 25325609 DERIVED

MeSH Terms

Conditions

Brain Injuries, Traumatic

Interventions

Modafinil

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Limitations and Caveats

The sponsor's decision to terminate the study early resulted in the small number of study participants, and related limitations to the interpretation of the study results.

Results Point of Contact

• Title: Manager, Biopharmaceutics
• Organization: Teva Pharmaceuticals USA

clinicaltrialqueries@tevausa.com

1-866-384-5525

Study Officials

• Sponsor's Medical Expert, MD

  Teva Branded Pharmaceutical Products R&D, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 9, 2009
• First Posted: September 24, 2009
• Study Start: August 31, 2009
• Primary Completion: January 31, 2011
• Study Completion: January 31, 2011
• Last Updated: December 17, 2021
• Results First Posted: October 18, 2013

Record last verified: 2021-12

Locations

US (61)