Rivastigmine Patch in Veterans With Cognitive Impairment Following TBI

Inclusion Criteria:

• Be a male or a female of any race

• Be outpatient Veterans residing in the community

• Be 19-65 years old at the time of inclusion

• Female patients of childbearing potential must have a negative pregnancy test atbaseline and must practice an acceptable method of birth control during the trial

• Satisfy the following diagnostic criteria:

• A history of previous head trauma(s) at least 12 months prior to study enrollmentas determined by TBI diagnostic assessment

• Closed head injury (non-penetrating) based on International Classification ofDisease (ICD) 9 CM (Clinical Modification) 10 diagnosis code 854.0 as determinedby TBI diagnostic assessment

• Meet or exceed the modified American Congress of Rehabilitation Medicines (ACRM)criteria for Mild TBI as determined by TBI diagnostic assessment

• Have a deficit in the area of verbal memory

• Have subjective memory impairment that was reported to be present from the time ofinjury or shortly thereafter to be associated with brain injury

• Satisfy the Diagnostic and Statistical Manual (DSM, 4th edition) for cognitivedisorder not otherwise specified, dementia due to TBI, or amnestic disorder due to TBI

• Demonstrate willingness to accept randomization

• Provide written informed consent to participate in the study

Exclusion Criteria:

• Have a medical condition that can interfere with the diagnostic process and theassessment of clinical and mental status, or possibly endanger their health. Suchconditions include, but are not limited to endocrinological, neurological (includingepilepsy), cardiovascular (including clinically significant bradyarrhythmia, restingheart rate <50 without a pacemaker or treating physician's approval), pulmonary,hematologic, hepatic, and renal conditions, and significant laboratory abnormalitiesas determined by Study Chair.

• Have a current diagnosis of any primary neurodegenerative disorder, includingHuntington's disease, Parkinson's disease, or DSM-IV-TR (Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition, Text Revision) dementia (other thanDementia Due to Head Trauma).

• Have suicidal ideations or have been judged to be a significant suicide risk perclinical judgment and the Columbia Suicide Severity Rating Scale (C-SSRS).

• Have a history of DSM-IV-TR substance (drug and/or alcohol) dependence disorder withinthe last 5 years or a history of a substance abuse disorder within the past 6 months.

• Have a DSM-IV-TR lifetime and current psychotic disorder (except lifetime depressionwith psychotic features), bipolar disorder, or pre-TBI onsetattention-deficit/hyperactivity disorder.

• Have current PTSD symptoms that can bias or interfere with cognitive and clinicalassessments as determined by study site PI.

• Have demonstrated suboptimal effort on cognitive testing as defined by:

1. Test of Memory Malingering (TOMM) raw score below 45 on either Trial 2 or theRetention Trial, or

2. Green's Medical Symptom Validity Test (MSVT) score of 85% on any one of theImmediate Recall, Delayed Recall, or Consistency indices.

• Have demonstrated a lack of tolerability to rivastigmine treatment in the past orsevere reactions to other cholinesterase inhibitors as determined by the siteinvestigator.

• Be taking medications that significantly affect cognitive functioning in TBIpopulation and/or may enhance the beneficial/adverse/toxic effect of rivastigmine orvice versa. These compounds include, but are not limited to, centrally-actinganticholinergic drugs (e.g., atropine), other cholinesterase inhibitors (e.g.,donepezil, galantamine), and agents that augment cerebral catecholaminergic function (e.g., psychostimulants, amantadine, memantine, selegiline, levodopa, etc). Subjectsreceiving modafinil may be considered for inclusion if they have been on a stable dosefor a minimum of 3 months, and if all inclusion criteria are met. Treatment ofnon-exclusionary comorbid psychiatric symptoms with compounds that include, but arenot limited to, antidepressants, anxiolytics, sedative-hypnotics, anticonvulsants, andatypical antipsychotics will be permitted provided that: 1) the site investigator,based on review of medical history, records, and current medications and inconsultation with the Study Chair, concludes that the agent(s) are neither cause(s) ofnor significant contributor(s) to the potential subject's memory impairment; 2) thedose of the agent(s) has been stable for the 3 months preceding study participation;and 3) the dose of the agent(s) remains stable, where clinically feasible, throughoutthe study. For medications prescribed for non-exclusionary conditions on as neededbasis, particularly when those medications include benzodiazepines, sympathomimetics,antitussive agents or potentially sedating analgesics - every use will be documentedby the subject and will not be taken within 24 hours of performing study-relatedcognitive testing. (Appendix A: Exclusionary Medications).

• Have been exposed to other cholinesterase inhibitors in the 30 days prior torandomization.

• Have a history of penetrating brain injury, cerebrovascular disease, cerebralneoplasm, major brain surgery, or multiple sclerosis.

• Have a significant visual or auditory deficit that may interfere with ability tocomplete study assessments.

• Have a limited ability to speak and read English.

• Be participating in another clinical trial with active intervention.