Phase 2 Randomized Controlled Trial of Sildenafil Citrate for Treatment of Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury
University of Pennsylvania
Summary
Traumatic Cerebral Vascular Injury (TCVI) is a common consequence of traumatic brain injury (TBI), including mild TBI (mTBI). TCVI is associated with poor recovery after TBI in animal models. TCVI can be measured non-invasively in humans, and therapies targeting TCVI are attractive candidates to ameliorate the consequences of TBI. Sildenafil potentiates nitric oxide (NO) dependent vasodilatation and is approved by the Food and Drug Administration (FDA) for the treatment of erectile dysfunction and primary pulmonary hypertension. In pre-clinical models of stroke, sildenafil improves cerebral blood flow (CBF), promotes, angiogenesis, neurogenesis and improves recovery. In an initial Phase 2a trial (NCT01762475) of sildenafil in patients with chronic moderate to severe TBI, the investigators found that low dose sildenafil (25 mg BID) therapy is safe and well tolerated, that a single dose of sildenafil 50 mg potentiates CVR in areas of the brain with dysfunctional endothelium, and that CVR is a reliable diagnostic marker of TCVI and has potential as a pharmacodynamic and predictive biomarker. In this proposal, the investigators will conduct a randomized clinical trial to determine the optimal PDE5 inhibitor dose to improve or normalize microvascular function (as measured by the change in CVR measurements before and after a single dose of sildenafil, or ΔCVR) using a range of sildenafil citrate doses: 20, 40, 80 mg) in chronic TBI patients. The investigators will also test the safety and tolerability of the same dose ranges of chronic (4-week) thrice daily sildenafil or placebo administration in chronic TBI patients and explore its effects on chronic symptoms and clinical outcomes.
Description
Objectives: Objective 1: To determine the optimal sildenafil dose to improve microvascular function (ΔCVR measure) after a single dose (dose range sildenafil 20-80 mg) in 160 chronic TBI patients. Objective 2: To assess the safety and tolerability of a range of PDE5 inhibitor doses (placebo, sildenafil 20, 40, 80 mg, administered orally three times daily (TID)) in 160 chronic TBI subjects. Objective 3 (exploratory): To measure the effect of chronic (4-week) PDE-5 inhibitor administration at 3 different doses compared to placebo on TBI symptom self-report, clinician-administered outcome meas…
Eligibility
- Age range
- 18–70 years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria To be eligible to participate in this study, an individual must meet all of the following criteria: 1. Provision of signed and dated informed consent form 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged 18-70 4. Defense Enrollment Eligibility Reporting System (DEERS) eligible (WRNMMC only; N/A for UPenn) 5. History of TBI greater than 6 months and less than 25 years prior to enrollment, based on the 2023 American Congress of Rehabilitation Medicine Criteria92; 1. Plausible Mechanism of Inj…
Interventions
- DrugSildenafil Citrate low dose
Sildenafil citrate 20 mg, oral, TID
- DrugPlacebo
Placebo, oral, TID
- DrugSildenafil medium dose
Sildenafil 40 mg, oral, TID
- DrugSildenafil high dose
Sildenafil 80 mg, oral, TID
Location
- University of PennsylvaniaPhiladelphia, Pennsylvania