Brawman-Mintzer_2021_J.Neurotrauma__

Cognitive impairment is common in veterans with histories of traumatic brain injury (TBI). Cholinergic deficits have been hypothesized as contributors to this impairment. We report the effects of cholinesterase inhibitor rivastigmine transdermal patch treatment in veterans with TBI and post-traumatic memory impairment. Our objective was to evaluate the efficacy and safety of 9.5 mg/24 hours (10cm2) rivastigmine patch in veterans of military conflicts with persistent moderate to severe memory impairment at least 12 weeks following TBI. This randomized, outpatient, double-blind, placebo-controlled 12-week trial with exploratory double-blind phase of additional 14 weeks was conducted at 5 VA Medical Centers, among veterans with closed, non-penetrating TBI who met or exceeded modified ACRM criteria for mild TBI with verbal memory deficits, as assessed by the Hopkins Verbal Learning Test, Revised (HVLT-R). Patients were randomized 1:1 to rivastigmine or matching placebo patches following 1-week single-blind, placebo run-in phase. At randomization, patients received 4.6 mg/24hr rivastigmine patches or matching placebo increased to 9.5 mg/24 hours patch after 4 weeks. The primary efficacy outcome measure was the proportion of participants who had at least 5-word improvement on HVLT-R Total Recall Index (Trials 1-3). A total 3671 participants were pre-screened, of whom 257 (7.0%) were screened; 96 (37%) randomized and 94 included in study analyses. The responder rates were 40.8% (20/49) and 51.1% (23/45) in rivastigmine and placebo groups respectively (p=0.41). A mixed-effect model including treatment, time, and treatment by time interaction indicated no significant difference in treatment effect over time between the groups (p=0.24). Overall, there were no significant differences in changes for all secondary outcomes between the rivastigmine and placebo groups. The most commonly observed AEs were application site reactions. This trial provides the largest sample to date of veterans with TBI and posttraumatic memory deficits enrolled in a pharmacological trial.