The National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke have called for pilot clinical trials to investigate pharmacological interventions to improve outcomes in pediatric patients following traumatic brain injury (TBI). The present application is targeted to this agenda. TBI is the leading cause of long term disability in children, with related costs exceeding over $12 billion a year. While no level of injury severity is completely free of consequences, the deficits associated with more severe injury have significance educational and vocational ramifications that continue years after injury. The neurobehavioral sequelae of TBI (e.g., poor working memory, difficulty in allocation of attention, depression) suggest the presence of executive deficits that are consistent with trauma commonly affecting the frontal brain regions. The literature demonstrates that frontal cortex activity, enervated by mesocortical dopamine projections, is critically involved in the strategic actions that are frequent diminished after TBI. Treatment with amantadine hydrochloride (AMH), a dopamine agonist, has been shown to improve behavioral symptoms and executive function in adults after brain injury. While AMH is used clinically in children, there is a dearth of rigorous studies that evaluate the true efficacy of this drug. Therefore, the goal of this pilot clinical study is to evaluate the overall safety and efficacy of AMH in improving the behavioral management, functional outcome, and neuropsychological status of children who have experienced TBI, and to use this information to organize and design a Phase III clinical trial of AMH.
The specific aims of this research include 1) To determine if treatment with AMH address frontal dysfunction begun > 6 months after TBI and maintained for 12 weeks is safe and effective when compared to standard clinical care; 2) To determine the sensitivity of specific neuropsychological instruments to assess outcome after treatment with AMH; and 3) To determine if variables related to either the injury or the subject impact treatment outcome. This randomized controlled study of AMH incorporates a repeated measures design. After screening procedures to document behavioral deficits suggesting executive dysfunction, we will stratify 120 children from 6 through 16 years into three age groups, randomizing subjects into a treatment or standard care group. All subjects will complete baseline and 12-week follow-up neuropsychological testing that provides a focused assessment of executive skills. In addition to demonstrating the safety and efficacy of AMH, we expect to identify complex interactions among injury- and treatment-related variables (age at injury, age at treatment, medication status, and injury severity). This information will optimize the design of Phase III clinical trials.
