Cognitive REmediation After Trauma Exposure Trial = CREATE Trial

NCT ID: NCT01416948

Last Updated: 2013-04-26

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-08-31
• Study Completion Date: 2013-03-31

Brief Summary

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).

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.

Conditions

Posttraumatic Stress Disorder; Traumatic Brain Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Sugar Pill

Group Type: PLACEBO_COMPARATOR

Placebo Capsule

Intervention Type: DRUG

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.

Galantamine

Group Type: ACTIVE_COMPARATOR

Galantamine 12 mg

Intervention Type: DRUG

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.

Methylphenidate

Group Type: EXPERIMENTAL

Methylphenidate Hydrochloride 20 mg

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Ritalin; Razadyne

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

U.S. Army Medical Research and Development Command

FED

Sponsor Role: collaborator

INTRuST, Post-Traumatic Stress Disorder - Traumatic Brain Injury Clinical Consortium

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Thomas W McAllister, M.D.

Role: PRINCIPAL_INVESTIGATOR

Dartmouth-Hitchcock Medical Center

Ross Zafonte, M.D.

Role: PRINCIPAL_INVESTIGATOR

Spaulding Rehabilitation Hospital

Locations

VA San Diego Healthcare System

San Diego, California, United States

Spaulding Rehabilitation Hospital

Boston, Massachusetts, United States

Manchester VA Medical Center

Manchester, New Hampshire, United States

Duke University

Durham, North Carolina, United States

University of Cincinnati

Cincinnati, Ohio, United States

Ralph H. Johnson VA Medical Center

Charleston, South Carolina, United States

White River Junction VA Medical Center

White River Junction, Vermont, United States

Countries

United States

Other Identifiers

INTRuST-CREATE

Identifier Type: -

Identifier Source: org_study_id