Sildenafil for Microvasculopathy in Chronic TBI

• Status: Not yet recruiting
• Trial end date: 2027-12-31
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Pennsylvania
• Collaborator: Walter Reed National Military Medical Center
• Treatments: Sildenafil Citrate

Criteria

Inclusion 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 18-55

4. DEERS eligible (WRNMMC only)

5. History of moderate or severe TBI by DoD-VA criteria greater than 6 months and less than 10 years prior to enrollment; as evidenced by any ONE of the following 3 criteria:

1. GCS 3 - 12 (GCS obtained in Emergency Room and noted in medical record)

2. Post-traumatic amnesia > 24 hours

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

4. and/or by the Ohio State TBI Identification Method.

6. Chronic persistent post-concussive symptoms (Symptom Score > 1 on at least 3 items from the Rivermead Post-Concussion Symptom Questionnaire)

7. Glasgow Outcome Scale-Extended (GOSE) between 5-7

8. Ability to take oral medication and be willing to adhere to the study intervention regimen

9. Ability to participate in and complete 2 MRIs including 5 CVR and ΔCVR measures and four 4-week treatment periods.

10. Fluent English speaker

11. Adequate hearing and vision on screening test and self-rating

Exclusion Criteria:

1. Contraindication to sildenafil which includes the following:

1. Current/ongoing (within past month) use of organic nitrate vasodilators

2. Current/ongoing (within past month) use of ritonavir (HIV-protease inhibitor)

3. Current/ongoing (within past month) use of erythromycin, ketoconazole, or itraconazole

4. Current/ongoing (within past month) use of cimetidine

5. Current resting hypotension (BP < 90/50 mm Hg)

6. Current severe renal insufficiency (Creatinine Clearance < 30mL/min)

7. Current hepatic cirrhosis

8. Current cardiac failure or coronary artery disease causing unstable angina

9. Retinitis pigmentosa

10. Known hypersensitivity or allergy to sildenafil of any of its components

11. History of melanoma or suspicious skin lesions for melanoma on skin examination

2. Daily therapy with a PDE5 inhibitor within the month prior to randomization

3. History of penetrating TBI

4. History of disabling neurological or psychiatric disorder not related to TBI

5. Active substance abuse or dependence during the past 6 months

6. Estimated preinjury intellectual level ≤70

7. Unlikely to comply with repeated follow-up assessments and medication regimen.

8. Not fluent in English language.

9. Failing score on the Word Memory Test of symptom validity.

10. Current inclusion in another interventional clinical trial

11. Subjects with metal implants that would interfere with the MR imaging procedures

12. History of priapism

13. Pregnant or breast-feeding women

14. Actively suicidal

15. History of hypertension requiring treatment

16. History of hyperlipidemia requiring treatment

17. History of diabetes mellitus requiring medical treatment