- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05782244
Sildenafil for Microvasculopathy in Chronic TBI
Phase 2 Randomized Controlled Trial of Sildenafil Citrate for Treatment of Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Objectives:
Objective 1: To determine the optimal sildenafil dose to improve microvascular function (ΔCVR measure) after a single dose (dose range sildenafil 20-80 mg) in 160 chronic TBI patients.
Objective 2: To assess the safety and tolerability of a range of PDE5 inhibitor doses (placebo, sildenafil 20, 40, 80 mg, administered orally three times daily (TID)) in 160 chronic TBI subjects.
Objective 3 (exploratory): To measure the effect of chronic (4-week) PDE-5 inhibitor administration at 3 different doses compared to placebo on TBI symptom self-report, clinician-administered outcome measures, and clinician interview-based impression of change.
Primary Endpoint: The primary outcome measure will be the baseline visit delta cerebrovascular reactivity (ΔCVR) or the difference between global CVR (mm/Hg) measured before and 1 hour after a randomized, double blind, oral administration of one of 3 doses of sildenafil (20mg, 40 mg or 80 mg) or placebo. CVR (mm/Hg) is an imaging measure of cerebral microvascular function and is measured in the MRI nd by the change in the fMRI-BOLD signal during a 7 minute 5% hypercapnia challenge (alternating inhalation of room air and room air enriched with 5% CO2 in a block design for 1 minute each over 7 minutes total).
Secondary Endpoints: The secondary outcome measures will be an assessment of study drug safety and tolerability. Safety will be measured by the number of participants with treatment-related adverse events as assessed by the CTCAE v4.0. Tolerability will be measured the number of participants with treatment-related adverse events as assessed by the CTCAE v4.0, self-report compliance with drug regimen and remaining pill count at the end of the study.
Exploratory Endpoints: Clinician administered and self-report measures of clinical symptom improvement, change in neurocognitive function and post-concussive symptoms improvement before and after 4 week sildenafil intervention. These will be measured by the change in baseline and end of treatment testing/reports of the following functional and symptom neurobehavioral measures: Clinician Interview-Based Impression (CIBI); Glasgow Outcome Scale-Extended (GOSE); Rivermead Post-Concussion Symptom Questionnaire (RPQ); Headache Impact Test-6 (HIT-6); PTSD Checklist for DSM-5- Civilian Version (PCL-5); Patient Health Questionnaire 9 (PHQ-9); Mental Fatigue Scale (MSF); NeuroQOL Short form for Positive Affect and Well Being; NeuroQOL Short form for Cognitive Functioning in Everyday Activities; Rey Auditory Verbal Learning Test (RAVLT); Brief Visuospatial Memory Test-Revised (BVMT-R); Trail Making Tests A and B (TMT); Processing Speed Index (PSI); Digit Symbol and Symbol Search of the Wechsler Adult Intelligence Scale (WAIS-IV); Simple and Complex Visual Reaction Time; Delis Kaplan Verbal Fluency Test (DKVFT); Grooved Pegboard Test; Brief Test of Adult Cognition by Telephone (BTACT).
Study Population: The study population for this protocol consists of 160 chronic TBI patients between the ages of 18 and 55 (both men and women) who have suffered a TBI more than 6 months before enrollment and remain symptomatic with at least 3 persistent post-concussive symptoms. The patients will be recruited from the University of Pennsylvania Health System (UPenn) and the Walter Reed National Military Medical Center (WRNMMC) TBI clinics and clinic referrals.
Phase: II
Description of Sites/Facilities : This is a two-site study, conducted at Penn Presbyterian Medical Center (PPMC), the Level I Trauma Center for UPenn, and WRNMMC, the flagship hospital for the Military Health System. Both PPMC and WRNMMC are major referral centers for TBI. The Clinical TBI Center at PPMC, led by Dr. Diaz-Arrastia, evaluates over 200 acute TBI cases admitted to the hospital per year and maintains an active outpatient TBI clinic that annually evaluates and treats over 800 unique TBI patients. WRNMMC is a tertiary referral center for active duty military personnel medically evacuated for TBI and has a specialized outpatient center for the evaluation and treatment of chronic TBI, the National Intrepid Center of Excellence (NICoE), which annually evaluates and treats 300-400 chronic TBI patients.
Enrolling Sites: Two (University of Pennsylvania Health System, Philadelphia, PA and Walter Reed National Military Medical Center, Bethesda, MD)
Description of Study Intervention: Sildenafil citrate is a phosphodiesterase-5 (PDE-5) inhibitor that is FDA-approved and widely used as a therapy for primary pulmonary hypertension and erectile dysfunction. Sildenafil or placebo will be administered at 3 doses (20mg, 40mg, 80mg) to the study participants to assess both single dose effect on CVR as well as safety, tolerability, and (as an exploratory measure) efficacy after 4-week thrice daily oral administration.
Study Duration: 48 months (i.e., 4 years)
Participant Duration:1 month
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Priyanka Kalyani, CCRP-PM, BS
- Phone Number: 267-271-9500
- Email: Priyanka.Kalyani@pennmedicine.upenn.edu
Study Locations
-
-
Pennsylvania
-
Philadelphia, Pennsylvania, United States, 19104
- Recruiting
- Penn Presbyterian Medical Center
-
Contact:
- Ramon Diaz-Arrastia, MD, PhD
- Phone Number: 800-789-7366
- Email: Ramon.Diaz-Arrastia@pennmedicine.upenn.edu
-
Principal Investigator:
- Ramon Diaz-Arrastia, MD, PhD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion 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 18-55
- DEERS eligible (WRNMMC only)
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:
- GCS 3 - 12 (GCS obtained in Emergency Room and noted in medical record)
- Post-traumatic amnesia > 24 hours
- TBI-related abnormality on neuroimaging (either CT or MRI)
- and/or by the Ohio State TBI Identification Method.
- Chronic persistent post-concussive symptoms (Symptom Score > 1 on at least 3 items from the Rivermead Post-Concussion Symptom Questionnaire)
- 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 2 MRIs including 5 CVR and ΔCVR measures and four 4-week treatment periods.
- Fluent English speaker
- Adequate hearing and vision on screening test and self-rating
Exclusion Criteria:
Contraindication to sildenafil which includes the following:
- Current/ongoing (within past month) use of organic nitrate vasodilators
- 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 (Creatinine Clearance < 30mL/min)
- 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 randomization
- 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
- Unlikely to comply with repeated follow-up assessments and medication regimen.
- Not fluent in English language.
- Failing score on the Word Memory Test of symptom validity.
- Current inclusion in another interventional clinical trial
- Subjects with metal implants that would interfere with the MR imaging procedures
- History of priapism
- Pregnant or breast-feeding women
- Actively suicidal
- History of hypertension requiring treatment
- History of hyperlipidemia requiring treatment
- History of diabetes mellitus requiring medical treatment
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Sildenafil citrate low dose
Sildenafil citrate 20 mg, oral, TID
|
Sildenafil citrate 20 mg, oral, TID
Other Names:
|
Placebo Comparator: Placebo
Placebo, oral, TID
|
Placebo, oral, TID
Other Names:
|
Active Comparator: Sildenafil citrate medium dose
Sildenafil citrate 40 mg, oral, TID
|
Sildenafil 40 mg, oral, TID
Other Names:
|
Active Comparator: Sildenafil citrate high dose
Sildenafil citrate 80 mg, oral, TID
|
Sildenafil 80 mg, oral, TID
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Optimal Dose
Time Frame: Assessed at baseline visit
|
Delta cerebrovascular reactivity (ΔCVR) after single-dose sildenafil administration during the neuroimaging session.
|
Assessed at baseline visit
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: Assessed over 4 week daily intervention of 3 doses of sildenafil in TBI patients
|
Safety will be measured by the number of participants with treatment-related adverse events as assessed by the CTCAE v4.0.
Tolerability will be measured the number of participants with treatment-related adverse events as assessed by the CTCAEv4.0, and by number of participants who did not complete the course of treatment.
Compliance will be measured by self-report compliance with drug regimen and pill counts remaining at the end of the study.
|
Assessed over 4 week daily intervention of 3 doses of sildenafil in TBI patients
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Clinician Interview-Based Impression (CIBI)
Time Frame: Assessed at baseline and at the end of the 4 week intervention.
|
Change in clinical status, neurocognitive function and post-concussive symptoms between baseline and completion of a 4 week sildenafil intervention, measured by the change in baseline and end of treatment using the Clinician Interview-Based Impression (CIBI) measure.
|
Assessed at baseline and at the end of the 4 week intervention.
|
Glasgow Outcome Scale-Extended (GOSE)
Time Frame: Assessed at baseline and at the end of the 4 week intervention.
|
Change in clinical status, neurocognitive function and post-concussive symptoms between baseline and completion of a 4 week sildenafil intervention, measured by the change in baseline and end of treatment using the Glasgow Outcome Scale-Extended (GOSE) measure.
|
Assessed at baseline and at the end of the 4 week intervention.
|
Rivermead Post-Concussion Questionnaire (RPQ)
Time Frame: Assessed at baseline and at the end of the 4 week intervention.
|
Change in clinical status, neurocognitive function and post-concussive symptoms between baseline and completion of a 4 week sildenafil intervention, measured by the change in baseline and end of treatment using the Rivermead Post-Concussion Questionnaire (RPQ) measure.
|
Assessed at baseline and at the end of the 4 week intervention.
|
Headache Impact Test-6 (HIT-6)
Time Frame: Assessed at baseline and at the end of the 4 week intervention.
|
Change in clinical status, neurocognitive function and post-concussive symptoms between baseline and completion of a 4 week sildenafil intervention, measured by the change in baseline and end of treatment using the Headache Impact Test-6 (HIT-6) measure.
|
Assessed at baseline and at the end of the 4 week intervention.
|
Mental Fatigue Scale (MSF)
Time Frame: Assessed at baseline and at the end of the 4 week intervention.
|
Change in clinical status, neurocognitive function and post-concussive symptoms between baseline and completion of a 4 week sildenafil intervention, measured by the change in baseline and end of treatment using the Mental Fatigue Scale (MSF) measure.
|
Assessed at baseline and at the end of the 4 week intervention.
|
Neuro-Quality of Life (NeuroQoL)
Time Frame: Assessed at baseline and at the end of the 4 week intervention.
|
Change in clinical status, neurocognitive function and post-concussive symptoms between baseline and completion of a 4 week sildenafil intervention, measured by the change in baseline and end of treatment using the NeuroQOL Short form for Affect and Well Being and NeuroQOL Short form for Cognitive Functioning.
|
Assessed at baseline and at the end of the 4 week intervention.
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Ramon Diaz-Arrastia, MD, PhD, University of Pennsylvania
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Wounds and Injuries
- Craniocerebral Trauma
- Trauma, Nervous System
- Brain Injuries
- Brain Injuries, Traumatic
- Molecular Mechanisms of Pharmacological Action
- Vasodilator Agents
- Urological Agents
- Enzyme Inhibitors
- Phosphodiesterase Inhibitors
- Phosphodiesterase 5 Inhibitors
- Sildenafil Citrate
Other Study ID Numbers
- 852199
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Traumatic Brain Injury
-
Fondazione per la Ricerca Ospedale MaggioreCompletedBrain Injuries, Traumatic | Brain Injury Traumatic Severe | Brain Injury Traumatic ModerateItaly
-
Toronto Rehabilitation InstituteCentre for Aging and Brain Health Innovation; Ontario Neurotrauma FoundationUnknownBrain Injuries, Traumatic | Brain Injury, Chronic | Brain Injury Traumatic Severe | Brain Injury Traumatic ModerateCanada
-
Hospital Sirio-LibanesUniversity of Sao Paulo; Ministry of Health, Brazil; Hospital Sao Rafael; PROAD... and other collaboratorsRecruitingBrain Injury Traumatic Severe | Brain Injury Traumatic Moderate | Post Traumatic EpilepsyBrazil
-
University of TurkuTurku University Hospital; The Finnish Funding Agency for Technology and Innovation... and other collaboratorsCompletedBrain Injuries | TBI (Traumatic Brain Injury) | Brain Injuries, Traumatic | Traumatic Brain Injury | Injury, Brain, TraumaticFinland
-
Children's Hospital Medical Center, CincinnatiUniversity of CincinnatiCompletedBrain Injury Traumatic MildUnited States
-
BrainScope Company, Inc.RecruitingTBI (Traumatic Brain Injury) | Concussion, Brain | MTBI - Mild Traumatic Brain Injury | Closed Head InjuryUnited States
-
Institut National de la Santé Et de la Recherche...Institut National de Recherche en Informatique et en AutomatiqueNot yet recruitingTBI (Traumatic Brain Injury)France
-
First Affiliated Hospital Xi'an Jiaotong UniversityXijing Hospital; Second Affiliated Hospital of Wenzhou Medical University; Central... and other collaboratorsRecruitingMTBI - Mild Traumatic Brain Injury | Moderate Traumatic Brain InjuryChina
-
First Affiliated Hospital Xi'an Jiaotong UniversityHealth Science Center of Xi'an Jiaotong University; The Second Affiliated Hospital...RecruitingMTBI - Mild Traumatic Brain InjuryChina
-
Perception Dynamics InstituteUniversity of California, San Diego; University of South Alabama; University...RecruitingMTBI - Mild Traumatic Brain InjuryUnited States
Clinical Trials on Sildenafil Citrate low dose
-
University of Mississippi Medical CenterActive, not recruiting
-
University of EdinburghPfizerCompletedHypertensionUnited Kingdom
-
Duke UniversityCompletedHand Foot Syndrome | Palmar Plantar ErythrodysesthesiaUnited States
-
Udo SechtemWithdrawn
-
University Hospital, AngersWithdrawnPeripheral Arterial Occlusive Disease
-
Pfizer's Upjohn has merged with Mylan to form Viatris...TerminatedPulmonary Arterial HypertensionHong Kong, Malaysia, Serbia, United States, Germany, Latvia, Australia, Croatia, Greece, Czechia, Bosnia and Herzegovina, Singapore, Belgium, Israel, Mexico, Poland, Romania, Russian Federation, South Africa, Spain, Thailand, Turkey, Ukrai...
-
Laboratório Teuto Brasileiro S/AUnknown
-
University Hospital, AngersCompletedPeripheral Arterial Occlusive Disease
-
Northwestern UniversityCompletedHand Foot Skin ReactionUnited States
-
Mayo ClinicTerminatedCongestive Heart Failure | Renal DysfunctionUnited States