RECRUITING

Sildenafil for Microvasculopathy in Chronic TBI

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

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.

Official Title

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

Quick Facts

Study Start:2024-07-02

Study Completion:2027-12-31

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05782244

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.

Ages Eligible for Study:18 Years to 70 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion 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	Pregnancy or breastfeeding Severe psychiatric disorders Active substance abuse Unstable medical conditions Inability to comply with study requirements

Inclusion Criteria

Exclusion 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

Pregnancy or breastfeeding
Severe psychiatric disorders
Active substance abuse
Unstable medical conditions
Inability to comply with study requirements

Contacts and Locations

Study Contact

TBIRI Research

CONTACT

267-271-4951

tbiresearch@pennmedicine.upenn.edu

Principal Investigator

Ramon Diaz-Arrastia, MD, PhD

PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Study Locations (Sites)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104

United States

Collaborators and Investigators

Sponsor: University of Pennsylvania

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

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2024-07-02

Study Completion Date2027-12-31

Study Record Updates

Study Start Date2024-07-02

Study Completion Date2027-12-31

Terms related to this study

Additional Relevant MeSH Terms

Traumatic Brain Injury