Sildenafil for Microvasculopathy in Chronic TBI
CVR-TBI
Phase 2 Randomized Controlled Trial of Sildenafil Citrate for Treatment of Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury
1 other identifier
interventional
160
1 country
1
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Jul 2024
Typical duration for phase_2
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 22, 2022
CompletedFirst Posted
Study publicly available on registry
March 23, 2023
CompletedStudy Start
First participant enrolled
July 2, 2024
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 31, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
December 31, 2027
December 10, 2025
December 1, 2025
3.5 years
November 22, 2022
December 3, 2025
Conditions
Outcome Measures
Primary Outcomes (1)
Optimal Dose
Delta cerebrovascular reactivity (ΔCVR) after single-dose sildenafil administration during the neuroimaging session.
Assessed at baseline visit
Secondary Outcomes (1)
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Assessed over 4 week daily intervention of 3 doses of sildenafil in TBI patients
Other Outcomes (2)
Clinician Interview-Based Impression (CIBI)
Assessed at baseline and at the end of the 4 week intervention.
Glasgow Outcome Scale-Extended (GOSE)
Assessed at baseline and at the end of the 4 week intervention.
Study Arms (4)
Sildenafil citrate low dose
ACTIVE COMPARATORSildenafil citrate 20 mg, oral, TID
Placebo
PLACEBO COMPARATORPlacebo, oral, TID
Sildenafil citrate medium dose
ACTIVE COMPARATORSildenafil citrate 40 mg, oral, TID
Sildenafil citrate high dose
ACTIVE COMPARATORSildenafil citrate 80 mg, oral, TID
Interventions
Sildenafil 40 mg, oral, TID
Sildenafil 80 mg, oral, TID
Sildenafil citrate 20 mg, oral, TID
Eligibility Criteria
You may qualify if:
- 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.
- +1 more criteria
You may not qualify if:
- 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
- +11 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
University of Pennsylvania
Philadelphia, Pennsylvania, 19104, United States
Related Publications (1)
Kalyani P, Lippa SM, Werner JK, Amyot F, Moore CB, Kenney K, Diaz-Arrastia R. Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury. Neurotherapeutics. 2023 Oct;20(6):1629-1640. doi: 10.1007/s13311-023-01430-z. Epub 2023 Sep 11.
PMID: 37697134DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Ramon Diaz-Arrastia, MD, PhD
University of Pennsylvania
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
November 22, 2022
First Posted
March 23, 2023
Study Start
July 2, 2024
Primary Completion (Estimated)
December 31, 2027
Study Completion (Estimated)
December 31, 2027
Last Updated
December 10, 2025
Record last verified: 2025-12