Background: Unfortunately, to date, all large clinical trials of drug therapies for traumatic brain injury (TBI) have failed. This large-scale failure of expensive clinical trials has forced a reevaluation of clinical studies in TBI. Multiple expert panels emphasize the critical need to first identify or subtype each TBI patient’s unique brain pathologies by noninvasive measures (e.g., imaging, blood, or physiologic biomarkers) so that treatments can be designed that address the specific underlying pathology causing the chronic symptoms. Additionally, once identified, that same biomarker can then be used to test candidate therapies in clinical trials as well as measure an individual’s response to a specific treatment in a clinical setting. This submission proposes to adopt those expert recommendations and target a common, if not universal, subtype (or endophenotype) of TBI, traumatic cerebrovascular injury (TCVI), or injury to the cerebral blood vessels as a result of a TBI. We then we propose to evaluate an imaging biomarker, cerebrovascular reactivity (CVR), a physiologic response of endothelial cells to a stress, hypercapnia, in all TBI severities, including the most common by far, mild TBI, to confirm our previous research that CVR is a valid diagnostic biomarker of TCVI in chronic moderate and severe TBI. In addition, we will use CVR to measure how well a drug, sildenafil, improves microvascular function in TBI patients with the TCVI endophenotype; for this we will use CVR as a pharmacodynamic biomarker that will tell us whether the drug is acting on a specific cell function that we have targeted for therapy in TBI patients with TCVI because it is chronically injured. Sildenafil is a type of drug called a phosphodiesterase 5 (PDE5) inhibitor that acts on endothelial cells and helps them dilate when injured or stressed. We will also test three different sildenafil doses to determine the minimal dose needed to get the maximal benefit on the injured cerebral microvasculature. This proposal builds on our prior Phase 2a study of sildenafil in chronic moderate-to-severe TBI patients (ClinicalTrials.gov NCT0l 762475). In that earlier study, we demonstrated that (1) CVR is universally decreased in patients with chronic moderate or severe TBI; (2) sildenafil improves CVR in these patients; and (3) 8-week treatment with sildenafil at a dose of 25 mg twice daily was well tolerated and is associated with a trend towards improvement in chronic TBI symptoms. This Phase 2b trial will lay the foundation for the design of a future definitive Phase 3 or large-scale clinical trial that will definitively test the efficacy of sildenafil on a clinical outcome measure in patients with chronic TBI of all severities.

Objectives: This study has three separate objectives or aims:

Specific Aim 1 (Primary Aim- Pharmacodynamic). To determine the optimal PDE5 inhibitor dose to improve microvascular function (L1CVR measures) after a single PDE5 inhibitor dose with the minimal drug side effects.

Specific Aim 2 (Primary Aim- Safety and Tolerability). To measure safety and tolerability of three sildenafil doses in 160 chronic TBI subjects over 4 weeks.

Specific Aim 3 (Secondary or Exploratory Aim). To measure the effect of chronic (4-week) sildenafil treatment at three different doses on TBI symptom self-report, cognitive, behavioral, and functional outcomes.

Study Design: A 4-week, placebo-controlled, double-masked dose finding and safety-tolerability study of approximately 160 participants with chronic TBI (i.e., a TBI that occurred between 6 months and 10 years ago and the individual is still having chronic symptoms from the TBI). Each participant will undergo a baseline evaluation including TBI history, presence of chronic TBI symptoms, and cognitive functioning. We will also measure CVR and CVR response (L1CVR) to a single sildenafil dose (0, 20, 40, or 80 mg) corresponding to the dose they will be randomized to on a TID schedule. Each participant will then take the drug for 4 weeks, and we will test safety and tolerability. We will use a special dose-escalating design to study whether all three doses are safe and tolerated.

Clinical Impact: We will use the results from this Phase 2b trial to design a future, definitive, large Phase 3 clinical trial that will test how well sildenafil improves clinical outcomes in patients with chronic TBI with TCVI. Additionally, it will further validate CVR and L1CVR (CVR measure before and after a single dose of sildenafil) as biomarkers of TCVI, thereby encouraging research on other TBI therapies aimed at improving microvascular dysfunction.

Relevance to Military Health: TBI is a frequent injury among both combat-deployed and training active-duty Service Members. As many as 30-40% of Service Members exposed to TBI suffer chronic symptoms and disability, adversely impacting military readiness and retention. Therapies aimed at improving neurologic functioning and relieving symptoms in the chronic stage after TBI have the potential to make a large and significant impact on the health of Service Members and military Veterans.