RecruitingPhase 2NCT05782244

Sildenafil for Microvasculopathy in Chronic TBI

Phase 2 Randomized Controlled Trial of Sildenafil Citrate for Treatment of Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury

Sponsor

University of Pennsylvania

Enrollment

160 participants

Start Date

Jul 2, 2024

Study Type

INTERVENTIONAL

Conditions

Traumatic Brain Injury

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.

Eligibility

Min Age: 18 YearsMax Age: 70 Years

Inclusion Criteria16

To be eligible to participate in this study, an individual must meet all of the following criteria:
Provision of signed and dated informed consent form
Stated willingness to comply with all study procedures and availability for the duration of the study
Male or female, aged 18-70
Defense Enrollment Eligibility Reporting System (DEERS) eligible (WRNMMC only; N/A for UPenn)
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;
Plausible Mechanism of Injury: Criterion 1 focuses on the external force that likely disrupted brain function, including blast/explosion forces and acknowledging intentional causes.
Clinical Signs: Criterion 2 highlights signs observed or elicited during examination, distinguishing them from subjective symptoms.
Acute Symptoms: Criterion 3 considers subjective acute symptoms, requiring at least two symptoms to be present.
Clinical Examination/Laboratory Findings: Criterion 4 is a new addition, incorporating findings like cognitive impairment or oculomotor impairment.
Neuroimaging: While not required for diagnosis, neuroimaging can be used to provide further evidence of brain injury.
Chronic persistent post-concussive symptoms (Symptom Score > 1 on at least 3 items from the Rivermead Post-Concussion Symptom Questionnaire; RPQ)
Glasgow Outcome Scale-Extended (GOSE) between 5-7
Ability to take oral medication and be willing to adhere to the study intervention regimen
Ability to participate in and complete 1 MRI including 2 CVR challenges and 4-week treatment period.
Adequate hearing and vision based on self-report and examiner's observation

Exclusion Criteria27

An individual who meets any of the following criteria will be excluded from participation in this study:
Contraindication to sildenafil which includes the following:
Current/ongoing (within past month) use of organic nitrate vasodilators or riociguat
Current/ongoing (within past month) use of ritonavir (HIV-protease inhibitor)
Current/ongoing (within past month) use of erythromycin, ketoconazole, or itraconazole
Current/ongoing (within past month) use of cimetidine
Current resting hypotension (BP < 90/50 mm Hg)
Current severe renal insufficiency
Current hepatic cirrhosis
Current cardiac failure or coronary artery disease causing unstable angina
Retinitis pigmentosa
Known hypersensitivity or allergy to sildenafil of any of its components
History of melanoma or suspicious skin lesions for melanoma on skin examination
Daily therapy with a PDE5 inhibitor within the month prior to consent
History of penetrating TBI
History of disabling neurological or psychiatric disorder not related to TBI
Active substance abuse or dependence during the past 6 months
Estimated preinjury intellectual level ≤70 (based on educational and vocational history)
Inability to understand written and spoken English, in the opinion of the investigator
Current inclusion in another interventional trial
Subjects with metal implants that would interfere with the MR imaging procedures
History of priapism
Pregnant or breast-feeding women
Actively suicidal (based on clinician assessment OR if patient endorses item 9 on Patient Health Questionnaire 9 (PHQ-9) and endorses suicidal ideation on Columbia Suicide Severity Rating Scale(CSSRS)
Hypertension requiring treatment with more than two antihypertensive drugs
Hyperlipidemia requiring treatment with more than one lipid lowering drug
Diabetes mellitus requiring medical treatment with insulin