Amantadine for the Treatment of Traumatic Brain Injury Irritability and Aggression: A Multi-site Study

This study has been completed.
Sponsor:
Collaborators:
Indiana University
University of Washington
The Institute for Rehabilitation and Research
Spaulding Rehabilitation Hospital
Ohio State University
Mount Sinai School of Medicine
Information provided by (Responsible Party):
Flora Hammond, Carolinas Healthcare System
ClinicalTrials.gov Identifier:
NCT00779324
First received: October 23, 2008
Last updated: February 12, 2014
Last verified: February 2014
  Purpose

The purpose of this study is to study the effect of amantadine on irritability and aggression caused by traumatic brain injury.


Condition Intervention
Brain Injury
Aggression
Drug: Amantadine Hydrochloride
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multi-Center, Parallel-Group, Randomized, Double-Blind, Placebo-Controlled Trial of Amantadine Hydrochloride in the Treatment of Chronic Traumatic Brain Injury Irritability and Aggression: A Replication Study

Resource links provided by NLM:


Further study details as provided by Carolinas Healthcare System:

Primary Outcome Measures:
  • Neuropsychiatric Inventory Irritability Domain [ Time Frame: 28 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Neuropsychiatric Inventory Aggression Domain [ Time Frame: 28 days and 60 days ] [ Designated as safety issue: No ]
  • State Anger Aggression Expression Inventory -- II [ Time Frame: 28 and 60 days ] [ Designated as safety issue: No ]
  • Neuropsychiatric Inventory Irritability Domain [ Time Frame: 60 days ] [ Designated as safety issue: No ]
  • Neuropsychiatric Inventory Caregiver Distress Score for Irritability and Aggression Domains [ Time Frame: 28 and 60 days ] [ Designated as safety issue: No ]
  • Clinical Global Impressions [ Time Frame: 28 and 60 days ] [ Designated as safety issue: No ]
  • Global Impression of Change [ Time Frame: 28 and 60 days ] [ Designated as safety issue: No ]
  • Short Form-12 [ Time Frame: 28 and 60 days ] [ Designated as safety issue: No ]
  • Satisfaction With Life Scale [ Time Frame: 28 and 60 days ] [ Designated as safety issue: No ]
  • Patient Health Questionnaire - 9 [ Time Frame: 28 and 60 days ] [ Designated as safety issue: No ]
  • Beck Depression Inventory II [ Time Frame: 28 and 60 days ] [ Designated as safety issue: No ]
  • Neuropsychologic tests [ Time Frame: 28 and 60 days ] [ Designated as safety issue: No ]
    Digit Span, Trail Making Test, Controlled Oral Word Association Test, California Verbal Learning Test, Processing Speed Index


Estimated Enrollment: 168
Study Start Date: August 2009
Study Completion Date: May 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Amantadine
Amantadine 100 mg every morning and Noon
Drug: Amantadine Hydrochloride
100 mg every morning and noon
Other Name: Symmetrel
Placebo Comparator: Placebo
Placebo tablets
Drug: Placebo
one placebo tablet every morning and 12 Noon

Detailed Description:

PURPOSE OF PROJECT: To study the effect of amantadine 100 mg administered twice daily compared to placebo on irritability from baseline to treatment Day 28.

SUMMARY OF PROJECT: It is anticipated that 168 subjects with 168 corresponding subject informants will be recruited for the study. Carolinas Rehabilitation, the lead center, and 5 collaborating centers will enroll approximately 28 subjects each.

Subjects will be recruited primarily from the clinics. Also, letters will be sent to patients in our data base. If the first encounter with research personnel is by telephone, the research assistant will obtain verbal (telephone) consent from the subject's informant for the Neuropsychiatric Inventory (NPI) for subject irritability. The score on this questionnaire must be ≥ 6 for qualification. This allows pre-screening to take place and avoid an unnecessary clinic visit.

Subjects who consent and qualify will be randomized in a 1:1 ratio, amantadine to placebo. Stratification to randomization group will occur based on the presence of depression defined by a Beck's Depression Inventory-II (BDI-II) score ≥ 13. Randomized subjects will receive amantadine or placebo 100 mg twice daily every morning and 12 Noon. There will be 4 clinic visits. Visits will occur at baseline, for consenting and screening, day 28, day 60 and day 90. At all 4 clinic visits, both the subject and the informant will be given questionnaires regarding the subject's behavior and mood. Follow up phone calls will occur each week that the subject is not seen in the clinic until the end of the study. Follow up phone calls will assess for study medication compliance, adverse events and concomitant medication changes. Day 60 ends the period of the Randomized Clinical Trial phase of the study and the subjects will begin the 1 month continuation phase of the study when all participants receive active amantadine.

The following questionnaires will be used as measures of irritability for the subject and the informant: Neuropsychiatric Inventory (NPI), State Trait Anger Expression Inventory (STAXI-2), and Global Impression of Change.

The following questionnaires will be dispensed to the subject only: Short Form -12, Satisfaction With Life Scale, Patient Health Questionnaire, Beck Depression Inventory, Brief Symptom Inventory, Family Assessment Device, Fatigue Impact Scale, and tests of cognitive function. The Glasgow Outcome Score-Extended will be completed by the research assistant using information obtained primarily from the informant.

The Investigator will complete the Clinical Global Impression of change at Visits 1, 2, 3, and 4.

History and Physical Exam, creatinine level (kidney function) will be obtained for safety and tolerability. Serum pregnancy tests will be drawn at screening for females of childbearing potential.

  Eligibility

Ages Eligible for Study:   16 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Closed head injury (defined as impaired brain function resulting from externally inflicted trauma without penetrating injury) at least 6 months prior to enrollment
  • Irritability that is either new or worse than the level of irritability before the traumatic brain injury, by report of the Observer or person with TBI
  • Age at time of enrollment: 16 to 75 years
  • Voluntary informed consent and authorization of participant and informant
  • Subject and informant willing to comply with the protocol
  • Informant-rated NPI Irritability Domain score 6 or greater (moderate-to-severe irritability)
  • Medically and neurologically stable during the month prior to enrollment
  • If taking antidepressant, anxiolytic, hypnotic, or stimulant medications, no change anticipated in these medications during the month prior to enrollment or during the 90-day participation
  • No change in therapies or medications planned during the 90-day participation
  • No surgeries planned during the 90-day participation
  • Vision, hearing, speech, motor function, and comprehension sufficient to complete interviews
  • Observer (e.g.: family member, close friend, employer) with whom subject interacts sufficiently to observe occurrences of irritability. The observer interacts with the participant for a period long enough and of a nature to be able to judge the participant's irritability. The interactions would need to be adequate to judge observer distress over the irritability, severity of irritability and frequency of irritability on the following scale: < once weekly; once per week; several times per week, but not every day; essentially continuous.

Exclusion Criteria:

  • Previous participation in the Carolinas TBI Model System amantadine irritability study
  • Ingestion of amantadine hydrochloride during the month prior to enrollment
  • Potential subject without a reliable informant
  • Penetrating head injury as defined by head injury due to gunshot, projectile or foreign object
  • Injury < 6 months prior to enrollment
  • Inability to interact sufficiently for communication with caregiver
  • Clinical signs of active infection
  • Diagnosis of seizure in the month prior to enrollment
  • Creatinine clearance <60 mL/min
  • Pregnancy (Beta-HCG + females of child-bearing potential) and lactating females
  • Concurrent use of first generation neuroleptic agents or phenelzine
  • History of schizophrenia or psychosis
  • Active concern of schizophrenia or psychosis
  • Diagnosis of progressive or additional neurologic disease that affects brain function, except stroke that occurs at th same time as the TBI
  • Previous allergy or adverse reaction to amantadine hydrochloride
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00779324

Locations
United States, Indiana
Indiana University and the Rehabilitation Hospital of Indiana
Indianapolis, Indiana, United States, 46254
United States, Massachusetts
Spaulding Rehabilitation
Boston, Massachusetts, United States, 02114
United States, North Carolina
Carolinas Rehabilitation
Charlotte, North Carolina, United States, 28203
United States, Ohio
The Ohio State University
Columbus, Ohio, United States, 43210
United States, Texas
TIRR Memorial Herman
Houston, Texas, United States, 77030
United States, Washington
University of Washington
Seattle, Washington, United States, 98195
Sponsors and Collaborators
Carolinas Healthcare System
Indiana University
University of Washington
The Institute for Rehabilitation and Research
Spaulding Rehabilitation Hospital
Ohio State University
Mount Sinai School of Medicine
Investigators
Principal Investigator: Flora M Hammond, MD Carolinas Rehabilitation
  More Information

Additional Information:
No publications provided

Responsible Party: Flora Hammond, Principal Investigator, Carolinas Healthcare System
ClinicalTrials.gov Identifier: NCT00779324     History of Changes
Other Study ID Numbers: 09-08-11B, NIDRR H133A080035
Study First Received: October 23, 2008
Last Updated: February 12, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Carolinas Healthcare System:
traumatic brain injury
irritability
aggression
amantadine
behavior

Additional relevant MeSH terms:
Aggression
Brain Injuries
Wounds and Injuries
Behavioral Symptoms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Amantadine
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on April 16, 2014