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

Status: Recruiting
Location: See location...
Intervention Type: Drug
Study Type: Interventional
Study Phase: Phase 2
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
Participation Requirements
Sex: All
Minimum Age: 18
Maximum Age: 70
Healthy Volunteers: f
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• 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; as evidenced by any ONE of the following 3 criteria:

∙ GCS 3 - 12 (GCS noted in medical record)

‣ Post-traumatic amnesia \> 24 hours

‣ TBI-related abnormality on neuroimaging (either CT or MRI)

• 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 2 MRIs including 5 CVR and ΔCVR measures and 4-week treatment period.

⁃ Adequate hearing and vision based on self-report and examiner's observation

Locations
United States
Pennsylvania
University of Pennsylvania
RECRUITING
Philadelphia
Contact Information
Primary
TBIRI Research
tbiresearch@pennmedicine.upenn.edu
267-271-4951
Time Frame
Start Date: 2024-07-02
Estimated Completion Date: 2027-12-31
Participants
Target number of participants: 160
Treatments
Active_comparator: Sildenafil citrate low dose
Sildenafil citrate 20 mg, oral, TID
Placebo_comparator: Placebo
Placebo, oral, TID
Active_comparator: Sildenafil citrate medium dose
Sildenafil citrate 40 mg, oral, TID
Active_comparator: Sildenafil citrate high dose
Sildenafil citrate 80 mg, oral, TID
Sponsors
Leads: University of Pennsylvania
Collaborators: Walter Reed National Military Medical Center

This content was sourced from clinicaltrials.gov