Sildenafil for Microvasculopathy in Chronic TBI

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.

Conditions

• Traumatic Brain Injury

Interventions

DRUG

Sildenafil Citrate low dose

Sildenafil citrate 20 mg, oral, TID

DRUG

Placebo

Placebo, oral, TID

DRUG

Sildenafil medium dose

Sildenafil 40 mg, oral, TID

DRUG

Sildenafil high dose

Sildenafil 80 mg, oral, TID

Sponsors & Collaborators

• Walter Reed National Military Medical Center

  collaborator FED

• University of Pennsylvania

  lead OTHER

Principal Investigators

• Ramon Diaz-Arrastia, MD, PhD · University of Pennsylvania

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

SEQUENTIAL

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2024-07-02

Primary Completion

2027-12-31

Completion

2027-12-31

FDA Drug

Yes

Countries

• United States

Study Locations