Cognitive REmediation After Trauma Exposure Trial = CREATE Trial

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.

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