Sildenafil for Microvasculopathy in Chronic TBI

Inclusion criteria

• To be eligible to participate in this study, an individual must meet all of the following criteria:
• 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, based on the 2023 American Congress of Rehabilitation Medicine Criteria92;
• Plausible Mechanism of Injury: Criterion 1 focuses on the external force that likely disrupted brain function, including blast/explosion forces and acknowledging intentional causes.
• Clinical Signs: Criterion 2 highlights signs observed or elicited during examination, distinguishing them from subjective symptoms.
• Acute Symptoms: Criterion 3 considers subjective acute symptoms, requiring at least two symptoms to be present.
• Clinical Examination/Laboratory Findings: Criterion 4 is a new addition, incorporating findings like cognitive impairment or oculomotor impairment.
• Neuroimaging: While not required for diagnosis, neuroimaging can be used to provide further evidence of brain injury.
• 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 1 MRI including 2 CVR challenges and 4-week treatment period.
• 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:
• Contraindication to sildenafil which includes the following:
• Current/ongoing (within past month) use of organic nitrate vasodilators or riociguat
• Current/ongoing (within past month) use of ritonavir (HIV-protease inhibitor)
• Current/ongoing (within past month) use of erythromycin, ketoconazole, or itraconazole
• Current/ongoing (within past month) use of cimetidine
• Current resting hypotension (BP \< 90/50 mm Hg)
• Current severe renal insufficiency
• Current hepatic cirrhosis
• Current cardiac failure or coronary artery disease causing unstable angina
• Retinitis pigmentosa
• Known hypersensitivity or allergy to sildenafil of any of its components
• History of melanoma or suspicious skin lesions for melanoma on skin examination
• Daily therapy with a PDE5 inhibitor within the month prior to consent
• History of penetrating TBI
• History of disabling neurological or psychiatric disorder not related to TBI
• Active substance abuse or dependence during the past 6 months
• Estimated preinjury intellectual level ≤70 (based on educational and vocational history)
• Inability to understand written and spoken English, in the opinion of the investigator
• Current inclusion in another interventional trial
• Subjects with metal implants that would interfere with the MR imaging procedures
• History of priapism
• Pregnant or breast-feeding women
• 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)
• Hypertension requiring treatment with more than two antihypertensive drugs
• Hyperlipidemia requiring treatment with more than one lipid lowering drug
• Diabetes mellitus requiring medical treatment with insulin