Cognitive REmediation After Trauma Exposure Trial = CREATE Trial

This study has been terminated.
(The funding agency, DoD, determined that the study could not meet its enrollment numbers by the end of the grant.)
Sponsor:
Collaborator:
U.S. Army Medical Research and Materiel Command
Information provided by (Responsible Party):
INTRuST, Post-Traumatic Stress Disorder - Traumatic Brain Injury Clinical Consortium
ClinicalTrials.gov Identifier:
NCT01416948
First received: August 12, 2011
Last updated: April 24, 2013
Last verified: April 2013
  Purpose

This study will evaluate the efficacy of methylphenidate and galantamine in the treatment of persistent cognitive symptoms associated with posttraumatic stress disorder (PTSD) and/or traumatic brain injury (TBI).


Condition Intervention Phase
Posttraumatic Stress Disorder
Traumatic Brain Injury
Drug: Methylphenidate Hydrochloride 20 mg
Drug: Placebo Capsule
Drug: Galantamine 12 mg
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Controlled Trial of Galantamine, Methylphenidate, and Placebo for the Treatment of Cognitive Symptoms in Patients With Traumatic Brain Injury (TBI) and/or Posttraumatic Stress Disorder (PTSD)

Resource links provided by NLM:


Further study details as provided by INTRuST, Post-Traumatic Stress Disorder - Traumatic Brain Injury Clinical Consortium:

Primary Outcome Measures:
  • Ruff Neurobehavioral Inventory - Postmorbid Cognitive Scale [ Time Frame: Baseline through Week 12 ] [ Designated as safety issue: No ]
    The Ruff Neurobehavioral Inventory (RNBI; Ruff & Hibbard, 2003) is a self-report instrument for assessment of a wide range of symptoms (cognitive, emotional, and physical), as well as quality of life and daily functioning. It was designed to assess these areas in individuals who have recently been affected by an injury, illness, or other stressor. The Postmorbid Cognitive scale will be used as the primary outcome measure in this study. The Postmorbid Cognitive scale consists of 24 items assessing Attention/Concentration, Executive Functions, Learning/Memory, and Speech/Language.


Secondary Outcome Measures:
  • Rivermead Postconcussion Symptom Questionnaire (RPCSQ) [ Time Frame: Baseline through week 12 ] [ Designated as safety issue: No ]
    The RPCSQ (N King, 1995), which can be self-administered or given by an interviewer, asks patients to rate the severity of 16 different symptoms commonly found after a mild traumatic brain injury. Patients are asked to rate the severity of each symptom over the past week and compare to the severity before their injury. This instrument will be used to determine the extent to which the broad spectrum of TBI symptoms respond to GAL and MPH.

  • Patient Health Questionnaire-9 (PHQ - 9) [ Time Frame: Baseline through week 12 ] [ Designated as safety issue: No ]
    The PHQ - 9 (Pfizer, 1999) is the self-administered 9 item depression scale of the Patient Health Questionnaire. This instrument will be used to determine the extent to which GAL and MPH improve depressive symptoms in participants with PTSD and/or TBI.

  • PTSD Checklist - Specific Event Version (PCL-S) [ Time Frame: Baseline through week 12 ] [ Designated as safety issue: No ]
    The PTSD Checklist - Specific Event Version (Weathers, 1993) is a 17 item self-report measure of DSM IV symptoms of PTSD in response to a specific event, used for screening and diagnosis of PTSD and monitoring symptom change during treament. This measure will be used to determine the extent to which the broad spectrum of PTSD symptoms responds to GAL and MPH.

  • PreMorbid-Postmorbid Difference Score on Cognitive Scale of Ruff Neurobehavioral Inventory [ Time Frame: Baseline through 12 weeks ] [ Designated as safety issue: No ]
    This measurement will be used to determine the extent to which GAL and MPH reduce the perceived difference between subjects' premorbid and postmorbid cognitive functioning.

  • Neuropsychological Tests of Memory, Attention and Other Executive Functions [ Time Frame: Baseline through 12 weeks ] [ Designated as safety issue: No ]
    These measurements will be used to determine the extent to which GAL and MPH affect objective cognitive functioning in participants with PTSD and/or TBI as measured on the following neuropsychological tests: Rey Verbal Auditory Learning Test; Trail Making Test; WAIS-III Processing Speed Index and Digit Span; Digit Vigilance test; WMS-III Letter-Number Sequencing; Brief Visuospatial Memory Test-Revised; Paced Auditory Serial Addition Test; Continuous Performance Test; and D-KEFS Verbal Fluency.


Enrollment: 32
Study Start Date: August 2011
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Sugar Pill Drug: Placebo Capsule
For patients randomly assigned to the placebo arm of the study, placebo will be administered BID at Week 0 through Week 12. Matching placebo will be administered to match the taper period.
Active Comparator: Galantamine Drug: Galantamine 12 mg
For patients randomly assigned to the GAL arm of the study, the drug will be initiated at 4 mg bid at week 0, increased to 8 mg bid at week 4, and finally increased to 12 mg bid at week 8 and then held constant until the major outcome assessment at week 12. The drug will be gradually tapered during weeks 12-14. If adverse events ensue, the subject's dose can be held at the current dose (rather than proceeding with scheduled dose increases) or reduced to the previous dose. Subjects who cannot tolerate the minimum dose (4 mg bid) will be withdrawn from the study.
Other Name: Razadyne
Experimental: Methylphenidate Drug: Methylphenidate Hydrochloride 20 mg
For patients assigned to the MPH arm of the study, the drug will be initiated at 5 mg bid at week 0, and increased to 10 mg bid at week 4, and finally increased to 20 mg bid at week 8 and then held constant until the major outcome assessment at week 12. The drug will be gradually tapered during weeks 12-14. If adverse events ensue, the subject's dose can be held at the current dose (rather than proceeding with scheduled dose increases) or reduced to the previous dose. Subjects who cannot tolerate the minimum dose (5 mg bid) will be withdrawn from the study.
Other Name: Ritalin

Detailed Description:

Both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are prevalent in service members returning from Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn (OEF/OIF/OND). Virtually all individuals who suffer TBI (TBI) have acute cognitive effects, and a significant number have persistent symptoms. A large number of individuals with PTSD also report problems with cognition, however, little is known about the treatment of cognitive complaints in either condition and less is known about cognitive complaints in individuals with co-occurring TBI and PTSD.

There is some preclinical evidence that both the cholinergic and catecholaminergic neurotransmitter systems play important roles in cognitive function in healthy individuals as well as those with mTBI and/or PTSD. We propose to evaluate the efficacy of two pharmacotherapies, one that predominantly augments cholinergic function (galantamine [GAL]) and one that augments predominantly catecholaminergic function (methylphenidate [MPH]), for reducing cognitive symptoms in individuals with TBI and/or PTSD.

Using a double-blind, randomized, placebo controlled design, 159 individuals with TBI and/or PTSD with persistent cognitive complaints will be randomized to receive galantamine 12 mg BID, methylphenidate 20 mg BID, or placebo for 12 weeks. The primary objective is to assess the efficacy of galantamine and methylphenidate in reducing cognitive complaints in patients with PTSD and/or TBI. Secondary objectives are to assess the extent to which non-cognitive distress responds to galantamine or methylphenidate, and assess the effect that galantamine and methylphenidate have on cognitive performance.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 18-55 years
  2. Has a DSM-IV diagnosis of chronic (≥ 3 months duration) PTSD and/or a history of TBI (≥ 3 months duration) as established by the INTRuST standard TBI Screening questionnaire.
  3. TBI must have occurred ≥ 90 days prior to the screening visit
  4. With either diagnosis (i.e., PTSD or TBI), the subject must have clinically significant cognitive complaints, as indicated by a T score ≥ 60 on the postmorbid Cognitive scale of the RNBI
  5. Interested in receiving treatment for cognitive symptoms
  6. Capable of giving informed consent

Exclusion Criteria:

  1. Known sensitivity, or previous adverse reaction(s), to GAL or other acetylcholinesterase inhibitors such as donepezil or rivastigmine OR Known sensitivity or previous adverse reactions to MPH or other stimulant medications (e.g., dextroamphetamine, long-acting methylphenidate preparations)
  2. Pregnant, likely to become pregnant, or lactating (female subjects only)
  3. Does not speak English
  4. WRAT scaled score < 70
  5. History of glaucoma
  6. History of cardiac conditions (e.g., bradycardia, AV block) or history of taking medications that are associated with conduction abnormalities
  7. History of seizure disorder (including post-traumatic epilepsy), neurosurgery, or neurodisability [Note that history of "impact seizure" is permitted]
  8. Lifetime history of psychotic disorder, Bipolar I, stimulant abuse or dependence, or tic disorder
  9. Alcohol dependence, alcohol abuse*, substance abuse, or substance dependence in the past 6 months [*Alcohol abuse will be defined as MINI diagnosis of "Alcohol Abuse" AND an AUDIT-C score of ≥ 5; Dawson, Grant, & Stinson, 2005].
  10. Current active suicidal ideation, or history of actual attempt within the past 10 years
  11. Current severe depressive symptoms, as indicated by a score of 20 or higher on the PHQ-9
  12. Current (or past 2-week) use of monoamine oxidase inhibitors [Washout period of at least 2 weeks is required]
  13. Current (or past 2-week) use of medications that potentiate cholinergic function (i.e., other cholinesterase inhibitors or procholinergic agents), or use of over-the-counter procholinergics [Washout period of at least 2 weeks is required]
  14. Current (or past 2-week) use of amphetamine-type stimulants or modafinil
  15. Current use of any other psychotropic medication that fails to meet the stabilization criterion of a minimum of 4 weeks on the same medication(s) and dose(s)
  16. Prior use of any other psychotropic medication that fails to meet the washout criterion of 2 weeks
  17. Concurrent cognitive therapy, that will not be discontinued at least 7 days prior to the baseline visit
  18. Baseline ECG and/or bloodwork reveals serious illness that precludes participation or use of study medications
  19. Any procedure requiring general anesthesia
  20. History of peptic ulcer disease or GI bleed or endoscopic procedure for GERD within the last year. Subjects taking physician prescribed treatment for GERD will be allowed to participate at the discretion of the PI after discussion with the primary treating physician.
  21. Current (or past 2-week) use of alpha 2 adrenergic agonists such as guanfacine
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01416948

Locations
United States, California
VA San Diego Healthcare System
San Diego, California, United States, 92161
United States, Massachusetts
Spaulding Rehabilitation Hospital
Boston, Massachusetts, United States, 02114
United States, New Hampshire
Manchester VA Medical Center
Manchester, New Hampshire, United States, 03104
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27710
United States, Ohio
University of Cincinnati
Cincinnati, Ohio, United States, 45219
United States, South Carolina
Ralph H. Johnson VA Medical Center
Charleston, South Carolina, United States, 29401
United States, Vermont
White River Junction VA Medical Center
White River Junction, Vermont, United States, 05009
Sponsors and Collaborators
INTRuST, Post-Traumatic Stress Disorder - Traumatic Brain Injury Clinical Consortium
U.S. Army Medical Research and Materiel Command
Investigators
Principal Investigator: Thomas W McAllister, M.D. Dartmouth-Hitchcock Medical Center
Principal Investigator: Ross Zafonte, M.D. Spaulding Rehabilitation Hospital
  More Information

No publications provided

Responsible Party: INTRuST, Post-Traumatic Stress Disorder - Traumatic Brain Injury Clinical Consortium
ClinicalTrials.gov Identifier: NCT01416948     History of Changes
Other Study ID Numbers: INTRuST-CREATE
Study First Received: August 12, 2011
Last Updated: April 24, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by INTRuST, Post-Traumatic Stress Disorder - Traumatic Brain Injury Clinical Consortium:
Cognitive Complaints, TBI, PTSD

Additional relevant MeSH terms:
Stress Disorders, Post-Traumatic
Stress Disorders, Traumatic
Brain Injuries
Wounds and Injuries
Anxiety Disorders
Mental Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Galantamine
Methylphenidate
Parasympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Nootropic Agents
Central Nervous System Agents
Therapeutic Uses
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Dopamine Uptake Inhibitors
Dopamine Agents
Neurotransmitter Uptake Inhibitors
Central Nervous System Stimulants

ClinicalTrials.gov processed this record on July 28, 2014