Rivastigmine Transdermal Patch Treatment for Moderate to Severe Cognitive Impairment in Veterans with Traumatic Brain Injury (RiVET Study): A Randomized Clinical Trial.

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 a 9.5 mg/24 h (10 cm2) rivastigmine patch in veterans of military conflicts with persistent moderate to severe memory impairment at least 12 weeks after TBI. This randomized, outpatient, double-blind, placebo-controlled 12-week trial with an exploratory double-blind phase of an additional 14 weeks was conducted at 5 VA Medical Centers, among veterans with closed, non-penetrating TBI who met or exceeded modified American Congress of Rehabilitation Medicine 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 after a 1-week single-blind, placebo run-in phase. At randomization, patients received 4.6 mg/24 h rivastigmine patches or matching placebo increased to a 9.5 mg/24 h patch after 4 weeks. The primary efficacy outcome measure was the proportion of participants who had at least a five-word improvement on the HVLT-R Total Recall Index (Trials 1-3). A total of 3671 participants were pre-screened, of whom 257 (7.0%) were screened; 96 (37%) randomized, and 94 included in study analyses. Responder rates were 40.8% (20 of 49) and 51.1% (23 of 45) in the 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 adverse events were application site reactions. This trial provides the largest sample to date of veterans with TBI and post-traumatic memory deficits enrolled in a pharmacological trial. Trial Registration: clinicaltrials.gov Identifier: NCT01670526.

Return of memory and sleep efficiency following moderate to severe closed head injury.

OBJECTIVE: Sleep disturbance is common in the subacute recovery phase following brain injury. A previous study from the authors' group found 68% of patients with closed head injury (CHI) had disrupted sleep on a rehabilitation unit. In the present study, the authors investigated whether improvement in sleep efficiency correlates with duration of posttraumatic amnesia (PTA) after CHI. METHODS: Fourteen CHI patients were enrolled and followed prospectively. Mechanism of injury included motor vehicle accident, fall, and blunt assault. An actigraph was placed on each subject's wrist within 72 hours of admission to the rehabilitation unit and recorded data for the duration of their stay. A minimum of 7 days of continuous actigraphy data was obtained on all subjects. PTA was measured daily using the Orientation Log (O-LOG). RESULTS: Seventy-eight percent of subjects had mean week-1 sleep efficiency scores of < or = 63%. Patients admitted having already cleared PTA had significantly better week-1 sleep efficiency scores than those with ongoing amnesia (P = .032). For those patients admitted with ongoing PTA, each 10-unit increase in sleep efficiency score correlated with 1 unit increase in O-LOG score (P = .056). CONCLUSIONS: Disrupted sleep is common in the postacute stage following CHI. Improved sleep efficiency correlates with resolution of PTA. Decreased sleep efficiency may negatively affect memory return after traumatic brain injury. Actigraphy is uniquely suited to study the sleep patterns of these patients.