Sildenafil for Microvasculopathy in Chronic TBI

Description

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

Talk to us

Study Overview

On this page

Study Details

Study overview

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

Sildenafil for Microvasculopathy in Chronic TBI

Condition
Traumatic Brain Injury
Intervention / Treatment

-

Contacts and Locations

Philadelphia

University of Pennsylvania, Philadelphia, Pennsylvania, United States, 19104

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

For general information about clinical research, read Learn About Studies.

Eligibility 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 18-70
  • 4. Defense Enrollment Eligibility Reporting System (DEERS) eligible (WRNMMC only; N/A for UPenn)
  • 5. 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:
  • 1. GCS 3 - 12 (GCS noted in medical record)
  • 2. Post-traumatic amnesia \> 24 hours
  • 3. TBI-related abnormality on neuroimaging (either CT or MRI)
  • 6. Chronic persistent post-concussive symptoms (Symptom Score \> 1 on at least 3 items from the Rivermead Post-Concussion Symptom Questionnaire; RPQ)
  • 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 4-week treatment period.
  • 10. Adequate hearing and vision based on self-report and examiner's observation
  • 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
  • 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 consent
  • 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 (based on educational and vocational history)
  • 7. Inability to understand written and spoken English, in the opinion of the investigator
  • 8. Current inclusion in another interventional trial
  • 9. Subjects with metal implants that would interfere with the MR imaging procedures
  • 10. History of priapism
  • 11. Pregnant or breast-feeding women
  • 12. 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)
  • 13. Hypertension requiring treatment with more than two antihypertensive drugs
  • 14. Hyperlipidemia requiring treatment with more than one lipid lowering drug
  • 15. Diabetes mellitus requiring medical treatment with insulin

Ages Eligible for Study

18 Years to 70 Years

Sexes Eligible for Study

ALL

Accepts Healthy Volunteers

No

Collaborators and Investigators

University of Pennsylvania,

Ramon Diaz-Arrastia, MD, PhD, PRINCIPAL_INVESTIGATOR, University of Pennsylvania

Study Record Dates

2027-12-31