Clinical trial NCT01416948: Cognitive REmediation After Trauma Exposure Trial = CREATE Trial
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Posttraumatic Stress Disorder
Traumatic Brain Injury
Keywords: Cognitive Complaints, TBI, PTSD
Lead sponsor: INTRuST, Post-Traumatic Stress Disorder - Traumatic Brain Injury Clinical Consortium
Sponsor class: OTHER
Collaborators: name: U.S. Army Medical Research and Development Command
First posted: 2011-08-15
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Ruff Neurobehavioral Inventory - Postmorbid Cognitive Scale
timeFrame: Baseline through Week 12
Secondary outcomes:
measure: Rivermead Postconcussion Symptom Questionnaire (RPCSQ)
timeFrame: Baseline through week 12
measure: Patient Health Questionnaire-9 (PHQ - 9)
timeFrame: Baseline through week 12
measure: PTSD Checklist - Specific Event Version (PCL-S)
timeFrame: Baseline through week 12
measure: PreMorbid-Postmorbid Difference Score on Cognitive Scale of Ruff Neurobehavioral Inventory
timeFrame: Baseline through 12 weeks
measure: Neuropsychological Tests of Memory, Attention and Other Executive Functions
timeFrame: Baseline through 12 weeks
Other outcomes:
Locations:
city: San Diego
country: United States
facility: VA San Diego Healthcare System
state: California
city: Boston
country: United States
facility: Spaulding Rehabilitation Hospital
state: Massachusetts
city: Manchester
country: United States
facility: Manchester VA Medical Center
state: New Hampshire
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center
state: South Carolina
city: White River Junction
country: United States
facility: White River Junction VA Medical Center
state: Vermont
Study officials:
affiliation: Dartmouth-Hitchcock Medical Center
name: Thomas W McAllister, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Spaulding Rehabilitation Hospital
name: Ross Zafonte, M.D.
role: PRINCIPAL_INVESTIGATOR
References: