Sildenafil for Traumatic Brain Injury

(CVR-TBI Trial)

Recruiting at 1 trial location

Overseen By TBIRI Research

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must not be taking: Nitrates, Ritonavir, Erythromycin, others

Disqualifiers: Severe renal insufficiency, Hepatic cirrhosis, Cardiac failure, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 4 weeks

160 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot participate if you are currently using certain medications like organic nitrate vasodilators, ritonavir, erythromycin, ketoconazole, itraconazole, or cimetidine within the past month. If you are on these medications, you would need to stop them to be eligible.

Is sildenafil generally safe for human use?

Sildenafil, known by various names like Viagra and Revatio, has been used by millions of people worldwide for erectile dysfunction and is generally well-tolerated. Most side effects are mild or moderate and rarely cause people to stop using it. ^{1 2 3 4 5}

How does the drug sildenafil work for traumatic brain injury?

Sildenafil is unique for traumatic brain injury because it targets traumatic cerebrovascular injury, a common issue in TBI, by enhancing the action of nitric oxide to improve blood flow in the brain. This approach is novel as it focuses on improving cerebrovascular reactivity, which is a potential biomarker for effective TBI treatment. ^{2 6 7 8 9}

Research Team

Ramon Diaz-Arrastia, MD, PhD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

This trial is for men and women aged 18-55 who have had a traumatic brain injury (TBI) with symptoms lasting long after the injury. They must be able to consent, follow study rules, and have TBI evidence on a CT or MRI scan or through specific identification methods. Participants should also have ongoing post-concussion symptoms and a moderate level of recovery.

Inclusion Criteria

Fluent English speaker

DEERS eligible (WRNMMC only)

Glasgow Outcome Scale-Extended (GOSE) between 5-7

Exclusion Criteria

History of priapism

Pregnant or breast-feeding women

Active substance abuse or dependence during the past 6 months

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo baseline assessments including neuroimaging to measure cerebrovascular reactivity (CVR) before and after a single dose of sildenafil or placebo

1 day

1 visit (in-person)

Treatment

Participants receive sildenafil or placebo thrice daily for 4 weeks to assess safety, tolerability, and effects on chronic symptoms

4 weeks

Weekly visits (in-person) for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of clinical status and neurocognitive function

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Placebo
• Sildenafil Citrate low dose
• Sildenafil high dose
• Sildenafil medium dose

Trial Overview The trial tests different doses of Sildenafil (20 mg, 40 mg, 80 mg) to see if they can improve blood flow in the brain's tiny vessels in chronic TBI patients. It compares these doses against a placebo over four weeks to check which dose might work best for improving microvascular function.

Participant Groups

Group I: Sildenafil citrate low dose Active Control 1 Intervention

Sildenafil citrate 20 mg, oral, TID

Group II: Sildenafil citrate medium dose Active Control 1 Intervention

Sildenafil citrate 40 mg, oral, TID

Group III: Sildenafil citrate high dose Active Control 1 Intervention

Sildenafil citrate 80 mg, oral, TID

Group IV: Placebo Placebo Group 1 Intervention

Placebo, oral, TID

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Walter Reed National Military Medical Center

Collaborator

Trials

149

Recruited

33,800+

Findings from Research

In a study of 30 patients with psychogenic erectile dysfunction, sildenafil citrate significantly improved nocturnal penile tumescence and rigidity compared to placebo, indicating its efficacy in enhancing erectile function.

The results suggest that performance anxiety may contribute to the lack of response to sildenafil in some patients, as significant improvements were observed when comparing sildenafil nights to placebo nights.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil citrate significantly improves nocturnal penile erections in sildenafil non-responding patients with psychogenic erectile dysfunction. Abdel-Naser, MB., Imam, A., Wollina, U.[2015]

In a 12-week study involving 254 men with erectile dysfunction in Egypt and South Africa, sildenafil (Viagra) significantly improved the ability to achieve and maintain erections compared to placebo, with 74% of sildenafil users reporting improved erections versus 27% for placebo (P<0.0001).

Sildenafil was found to be well-tolerated, with common side effects including headache, dyspepsia, and flushing, confirming its efficacy and safety profile consistent with previous global studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men in Egypt and South Africa. Levinson, IP., Khalaf, IM., Shaeer, KZ., et al.[2015]

In a 6-month study involving men with erectile dysfunction, vardenafil showed significant improvements in erectile function and sexual performance compared to placebo, with effects sustained or increased over time.

Vardenafil was well tolerated, with most side effects being mild or moderate, and the incidence of these side effects decreased over the study period, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial. Hellstrom, WJ., Gittelman, M., Karlin, G., et al.[2019]

In a study of 233 men with erectile dysfunction, 93% reported improved erections after 16 weeks of treatment with oral Viagra (sildenafil), demonstrating its long-term efficacy and safety.

During a subsequent withdrawal phase, those who continued sildenafil maintained their improvements in erectile function, while those switched to placebo returned to pre-treatment levels, indicating that ongoing treatment is necessary for sustained benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of oral Viagra (sildenafil citrate) in men with erectile dysfunction and the effect of randomised treatment withdrawal. Christiansen, E., Guirguis, WR., Cox, D., et al.[2019]

Sildenafil citrate (Viagra) has been prescribed to over 10 million patients and has shown significant improvements in erectile function across various conditions, including diabetes and cardiovascular disease, based on clinical trials.

The medication is generally well-tolerated, with most side effects being mild or moderate and rarely causing patients to stop treatment, indicating its safety in a wide range of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-year update of sildenafil citrate (Viagra) efficacy and safety. Sadovsky, R., Miller, T., Moskowitz, M., et al.[2022]

A phase II dose-finding study will investigate the effects of sildenafil, a PDE-5 inhibitor, on cerebrovascular reactivity (CVR) in 160 chronic TBI patients, focusing on optimizing dosage for improved CVR, which is a potential biomarker for traumatic cerebrovascular injury.

The study aims to assess the safety, tolerability, and clinical efficacy of sildenafil over a 4-week period, highlighting the importance of biomarker-informed approaches in developing effective treatments for traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury. Kalyani, P., Lippa, SM., Werner, JK., et al.[2023]

A single dose of sildenafil significantly improved cerebrovascular reactivity (CVR) in chronic traumatic brain injury (TBI) patients, indicating its potential as a treatment for cerebrovascular issues following TBI.

The 8-week administration of sildenafil was well tolerated in chronic TBI patients, with a trend towards clinical improvement in symptoms, suggesting its safety and potential efficacy for long-term management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phosphodiesterase-5 inhibition potentiates cerebrovascular reactivity in chronic traumatic brain injury. Kenney, K., Amyot, F., Moore, C., et al.[2023]

Sildenafil, a PDE5 inhibitor that can cross the blood-brain barrier, shows promise as a neuroprotective agent for preventing or repairing brain injuries such as stroke and traumatic brain injury, based on preclinical data.

The review highlights the potential benefits of combining sildenafil with existing treatments to enhance therapeutic outcomes for brain injuries, suggesting a novel approach to managing these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil-Mediated Neuroprotection from Adult to Neonatal Brain Injury: Evidence, Mechanisms, and Future Translation. Zinni, M., Pansiot, J., Léger, PL., et al.[2021]

The new sildenafil spray demonstrated equivalent bioavailability to the traditional tablet form, but it allowed for a faster onset of action, with maximum concentration reached in 51 minutes compared to 62 minutes for the tablet.

Most adverse events reported during the studies were mild to moderate, indicating that the new spray form is generally safe for use in healthy male volunteers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacokinetic features of sildenafil spray in healthy men depending on food intake]. Krivoborodov, GG., Zakharov, KA., Vasilyuk, VB., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Sildenafil citrate significantly improves nocturnal penile erections in sildenafil non-responding patients with psychogenic erectile dysfunction. [2015]

2. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men in Egypt and South Africa. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of oral Viagra (sildenafil citrate) in men with erectile dysfunction and the effect of randomised treatment withdrawal. [2019]

5. India pubmed.ncbi.nlm.nih.gov

Three-year update of sildenafil citrate (Viagra) efficacy and safety. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Phosphodiesterase-5 inhibition potentiates cerebrovascular reactivity in chronic traumatic brain injury. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Sildenafil-Mediated Neuroprotection from Adult to Neonatal Brain Injury: Evidence, Mechanisms, and Future Translation. [2021]

9. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Pharmacokinetic features of sildenafil spray in healthy men depending on food intake]. [2022]