Rivastigmine Patch in Veterans With Cognitive Impairment Following TBI
Condition: Traumatic Brain Injury; Cognitive Impairment
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Cognitive Dysfunction
Intervention: Rivastigmine Transdermal Patch
Intervention description: Cholinesterase Inhibitor
Intervention MeSH terms: Rivastigmine; Cholinesterase Inhibitors
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 94.0
Sex: All
Minimum age: 19 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Traumatic Brain Injury; Cognitive Impairment; Rivastigmine; Pharmacologic Actions; TBI; Memory; Cholinesterase Inhibitors; Cognition; Head Trauma

Summary:

      Difficulties with intellectual functioning, particularly memory functions, are common and
      source of long-term disability after Traumatic Brain Injury (TBI). However, there is very
      little information about pharmacologic (i.e., medication) treatments targeting these
      deficits. There are growing data showing brain abnormalities in acetylcholine, the chemical
      system that manages memory, in TBI. These findings provide the rationale for the use of
      cholinesterase inhibitors, medications that modulate this system, in TBI patients. As the
      prevalence of TBI among Veterans of recent military conflicts increases, becoming a
      "signature injury" of the Iraq and Afghanistan conflicts, it is of utmost importance to the
      Veterans Health Administration to collect scientific data on the efficacy of pharmacological
      treatments for intellectual difficulties in TBI patients. This study will evaluate the
      effects of the cholinesterase inhibitor rivastigmine transdermal patch in Veterans with TBI
      and posttraumatic memory problems. Results will provide much needed data that will help treat
      Veterans with TBI.
    

Eligibility criteria:

        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 at
             baseline 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 enrollment
                  as determined by TBI diagnostic assessment

               -  Closed head injury (non-penetrating) based on International Classification of
                  Disease (ICD) 9 CM (Clinical Modification) 10 diagnosis code 854.0 as determined
                  by 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 of
             injury or shortly thereafter to be associated with brain injury

          -  Satisfy the Diagnostic and Statistical Manual (DSM, 4th edition) for cognitive
             disorder 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 the
             assessment of clinical and mental status, or possibly endanger their health. Such
             conditions include, but are not limited to endocrinological, neurological (including
             epilepsy), cardiovascular (including clinically significant bradyarrhythmia, resting
             heart rate <50 without a pacemaker or treating physician's approval), pulmonary,
             hematologic, hepatic, and renal conditions, and significant laboratory abnormalities
             as determined by Study Chair.

          -  Have a current diagnosis of any primary neurodegenerative disorder, including
             Huntington's disease, Parkinson's disease, or DSM-IV-TR (Diagnostic and Statistical
             Manual of Mental Disorders, Fourth Edition, Text Revision) dementia (other than
             Dementia Due to Head Trauma).

          -  Have suicidal ideations or have been judged to be a significant suicide risk per
             clinical judgment and the Columbia Suicide Severity Rating Scale (C-SSRS).

          -  Have a history of DSM-IV-TR substance (drug and/or alcohol) dependence disorder within
             the 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 depression
             with psychotic features), bipolar disorder, or pre-TBI onset
             attention-deficit/hyperactivity disorder.

          -  Have current PTSD symptoms that can bias or interfere with cognitive and clinical
             assessments 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 the
                  Retention Trial, or

               2. Green's Medical Symptom Validity Test (MSVT) score of 85% on any one of the
                  Immediate Recall, Delayed Recall, or Consistency indices.

          -  Have demonstrated a lack of tolerability to rivastigmine treatment in the past or
             severe reactions to other cholinesterase inhibitors as determined by the site
             investigator.

          -  Be taking medications that significantly affect cognitive functioning in TBI
             population and/or may enhance the beneficial/adverse/toxic effect of rivastigmine or
             vice versa. These compounds include, but are not limited to, centrally-acting
             anticholinergic 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). Subjects
             receiving modafinil may be considered for inclusion if they have been on a stable dose
             for a minimum of 3 months, and if all inclusion criteria are met. Treatment of
             non-exclusionary comorbid psychiatric symptoms with compounds that include, but are
             not limited to, antidepressants, anxiolytics, sedative-hypnotics, anticonvulsants, and
             atypical antipsychotics will be permitted provided that: 1) the site investigator,
             based on review of medical history, records, and current medications and in
             consultation with the Study Chair, concludes that the agent(s) are neither cause(s) of
             nor significant contributor(s) to the potential subject's memory impairment; 2) the
             dose 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, throughout
             the study. For medications prescribed for non-exclusionary conditions on as needed
             basis, particularly when those medications include benzodiazepines, sympathomimetics,
             antitussive agents or potentially sedating analgesics - every use will be documented
             by the subject and will not be taken within 24 hours of performing study-related
             cognitive testing. (Appendix A: Exclusionary Medications).

          -  Have been exposed to other cholinesterase inhibitors in the 30 days prior to
             randomization.

          -  Have a history of penetrating brain injury, cerebrovascular disease, cerebral
             neoplasm, major brain surgery, or multiple sclerosis.

          -  Have a significant visual or auditory deficit that may interfere with ability to
             complete study assessments.

          -  Have a limited ability to speak and read English.

          -  Be participating in another clinical trial with active intervention.