Using Sildenafil to Improve Blood Flow in Chronic Traumatic Brain Injury

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

This study is testing whether sildenafil can improve blood flow in people with chronic traumatic brain injury to see if it helps their symptoms.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 160 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: University of Pennsylvania (Academic / other)
• Locations: 1 site (Philadelphia, Pennsylvania)
• Trial ID: NCT05782244 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to evaluate the effects of sildenafil on microvascular function in patients with chronic traumatic brain injury (TBI). It will assess the optimal dosage of sildenafil to enhance cerebrovascular reactivity through a randomized, double-blind, placebo-controlled design. The study will involve 160 participants who will receive varying doses of sildenafil or placebo, with outcomes measured through MRI imaging and self-reported symptoms. The trial also seeks to ensure the safety and tolerability of the treatment over a four-week period.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18-70 with a history of TBI and persistent post-concussive symptoms.

Not a fit: Patients with acute TBI or those who do not meet the eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve recovery and quality of life for patients suffering from chronic TBI.

How similar studies have performed: Previous studies have shown promising results with sildenafil in improving cerebral blood flow in related conditions, suggesting potential for success in this approach.

Eligibility criteria

Inclusion Criteria

To be eligible to participate in this study, an individual must meet all of the following 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, based on the 2023 American Congress of Rehabilitation Medicine Criteria92;

   1. Plausible Mechanism of Injury: Criterion 1 focuses on the external force that likely disrupted brain function, including blast/explosion forces and acknowledging intentional causes.
   2. Clinical Signs: Criterion 2 highlights signs observed or elicited during examination, distinguishing them from subjective symptoms.
   3. Acute Symptoms: Criterion 3 considers subjective acute symptoms, requiring at least two symptoms to be present.
   4. Clinical Examination/Laboratory Findings: Criterion 4 is a new addition, incorporating findings like cognitive impairment or oculomotor impairment.
   5. Neuroimaging: While not required for diagnosis, neuroimaging can be used to provide further evidence of brain injury.
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 1 MRI including 2 CVR challenges and 4-week treatment period.
10. Adequate hearing and vision based on self-report and examiner's observation

Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Contraindication to sildenafil which includes the following:

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

Where this trial is running

Philadelphia, Pennsylvania

• University of Pennsylvania — Philadelphia, Pennsylvania, United States (Recruiting)

Study contacts

• Principal investigator: Ramon Diaz-Arrastia, MD, PhD — University of Pennsylvania
• Study coordinator: TBIRI Research

Conditions Traumatic Brain Injury