Cognitive REmediation After Trauma Exposure Trial = CREATE Trial

Condition(s) targeted: Posttraumatic Stress Disorder; Traumatic Brain Injury

Intervention: Methylphenidate Hydrochloride 20 mg (Drug); Placebo Capsule (Drug); Galantamine 12 mg (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: INTRuST, Post-Traumatic Stress Disorder - Traumatic Brain Injury Clinical Consortium

Official(s) and/or principal investigator(s):
Thomas W McAllister, M.D., Principal Investigator, Affiliation: Dartmouth-Hitchcock Medical Center
Ross Zafonte, M.D., Principal Investigator, Affiliation: Spaulding Rehabilitation Hospital

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).

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)

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Ruff Neurobehavioral Inventory - Postmorbid Cognitive Scale

Secondary outcome:

Rivermead Postconcussion Symptom Questionnaire (RPCSQ)

Patient Health Questionnaire-9 (PHQ - 9)

PTSD Checklist - Specific Event Version (PCL-S)

PreMorbid-Postmorbid Difference Score on Cognitive Scale of Ruff Neurobehavioral Inventory

Neuropsychological Tests of Memory, Attention and Other Executive Functions

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.

Minimum age: 18 Years. Maximum age: 55 Years. Gender(s): Both.

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

VA San Diego Healthcare System, San Diego, California 92161, United States; Recruiting
Kathleen Gaa, Phone: 619-543-6179, Email: kgaa@ucsd.edu
Jody DeLaPena Murphy, MBA, Phone: 619-543-6102, Email: jodelapena@ucsd.edu
James Lohr, MD, Principal Investigator

Spaulding Rehabilitation Hospital, Boston, Massachusetts 02114, United States; Recruiting
Judith Frazier, Phone: 617-573-2478, Email: jfrazier2@partners.org
Laura Burns, Phone: 617-573-2237, Email: lburns2@partners.org
Ross Zafonte, DO, Principal Investigator

Manchester VA Medical Center, Manchester, New Hampshire 03104, United States; Recruiting
Beverlee Ross, Phone: 603-624-4366, Ext: 6817, Email: beverlee.ross@va.gov
Mike Macklin, Phone: 603-624-4366, Ext: 6815, Email: mike.macklin@va.gov
Roseanne Schipani, MD, Principal Investigator

Duke University, Durham, North Carolina 27710, United States; Recruiting
Kara Richardson, Phone: 919-684-2800, Email: kara.richardson@duke.edu
Gerald Grant, MD, Principal Investigator

University of Cincinnati, Cincinnati, Ohio 45219, United States; Recruiting
Carolyn Koenig, RN, Phone: 513-558-3518, Email: koenigch@UCMAIL.UC.EDU
Ian Jansen, Phone: 513-558-3546, Email: jansenih@ucmail.uc.edu
Lori Shutter, MD, Principal Investigator

Ralph H. Johnson VA Medical Center, Charleston, South Carolina 29401, United States; Recruiting
Matthew Schmidt, Phone: 843-876-5141, Email: schmidm@musc.edu
Kate Beaver, Phone: 843-792-8274, Email: kate.beaver@scra.org
Mark S George, MD, Principal Investigator

White River Junction VA Medical Center, White River Junction, Vermont 05009, United States; Recruiting
Leigh Chesnut, Phone: 802-295-9363, Ext: 5415, Email: Leigh.A.Chesnut@hitchcock.org
Mary Hynes, RN, MPH, Phone: 603-650-7552, Email: Mary.L.Hynes@hitchcock.org
Lanier Summerall, MD, MPH, Principal Investigator

Starting date: August 2011
Last updated: June 20, 2012