Angiotensin-(1-7): A Treatment for Neuropsychological and Memory Impairments Following Moderate to Severe Traumatic Brain Injury
Abstract
Traumatic brain injury (TBI) is a disruption in the normal function of the brain most commonly caused by a blow, bump, or jolt to the head; an object suddenly and violently hitting the head; or, an object piercing the skull and entering brain tissue. Moderate to severe TBI often results in life-changing neuropsychological impairment, including persistent problems with memory, attention span, and executive function. Furthermore, there is substantial evidence linking increases in systemic inflammation to impairment in cognitive function. Clinical studies with TBI patients have shown that increases in inflammatory factors are strongly correlated with a decrease in cognitive performance. In addition, TBI is recognized as one of the most common injuries sustained by members of the military. Despite improvements in body armor that have increased the survival rate for injured Service Members, the large percentage of Service Members that continue to sustain TBI and subsequent cognitive impairment highlights the need for new treatments for TBI. Thus, there is an immediate need to find safe, novel treatments to reduce or prevent cognitive impairment in military and non-military individuals with TBI. Angiotensin-1-7 (Ang-(1-7), which is a protein naturally present in the human body, has been shown to be effective in reducing the impact of inflammation in the brain. It has already been shown to be effective in reducing damage in heart and cancer patients. Our research at the University of Arizona also shows that Ang-(1-7) reduces the effect of trauma on cognitive functions in animals, but it has never been tested in humans. In this study, we will test the hypothesis that treatment with Ang-(1-7) initiated within 48 hours of injury and continued for 21 days will improve cognitive function in patients with moderate to severe TBI. We have two key objectives. The first to see whether the drug is safe in humans and what dosage of drug is tolerable. The second is to determine the effects of the drug to be given to TBI patients over 21 days of treatment and how their cognitive functions change. This is a feasibility study using a three-arm placebo, Ang-(1-7) 100 ug, Ang-(1-7) 200 ug parallel randomized controlled design. We chose this design to run the definitive trial in miniature so that we can reliably address the aims of our feasibility study, which are to give assurance that the Ang-(1-7) treatment is safe for TBI patients and that TBI patients can tolerate the Ang-(1-7) treatment, as well as answer whether there is any preliminary evidence that the treatment is effective. We plan to randomize 30 patients to each group. Arms will include saline placebo, Ang-(1-7) 100 micrograms/kg/day, and Ang-(1-7) 200 micrograms/kg/day injected subcutaneously daily for 21 days post-injury or discharge, whichever comes first. Injections will begin no later than 48 hours post-injury and continue for 21 days. The study will last for 4 years. In this study, we will follow the principles of community-based participatory research (CBPR) and will ensure a comprehensive involvement of diverse communities and patients in the implementation of the study. To achieve the goals of CBPR, we will engage in three sets of activities. First, we will create an active Community Advisory Board (CAB) consisting of Lived Experience Consultation community members. Fortunately, one of our local patient advocacy organizations has agreed to provide a representative who has had TBI as well as linking us with a TBI patient who will serve as a member of the CAB. Second, we work closely with local communities, including Native American and Hispanic communities, to include their views in shaping the study and to collaborate with them to provide TBI prevention programs. Finally, we will engage with the state-wide Arizona Biomedical Research Commission and related statewide institutions to ensure that the study is informed by the regulations and policies of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311077
Entities
People
- Bellal Joseph
Organizations
- United States Army
- University of Arizona