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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of sildenafil for improving blood flow in the brains of individuals with long-term symptoms from a traumatic brain injury (TBI). Researchers are testing various doses of sildenafil, a medication known for treating other conditions, to assess its potential in aiding recovery. Participants will receive either a low, medium, or high dose of sildenafil, or a placebo (an inactive substance), over four weeks. Ideal candidates are those who have experienced persistent TBI symptoms for more than six months. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group, offering participants an opportunity to contribute to significant advancements in TBI recovery.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that sildenafil is generally safe for people with traumatic brain injuries. In a previous study, patients with moderate to severe brain injuries took low doses of sildenafil and did not experience major side effects.

The FDA has already approved sildenafil for treating erectile dysfunction and a type of high blood pressure in the lungs, providing safety information from its use in humans. Studies have indicated that even with eight weeks of use, sildenafil did not cause serious problems.

During trials, researchers assessed the safety of sildenafil by counting how many participants experienced side effects related to the treatment. These studies used doses similar to those in the current trial, and no major safety concerns emerged. This suggests that sildenafil should be safe for most people to try in this context. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for traumatic brain injury that often focus on managing symptoms and preventing complications, sildenafil citrate is being explored for its potential to enhance blood flow and promote brain healing. Researchers are excited about sildenafil because it acts as a vasodilator, increasing blood flow to the brain, which could help improve recovery after injury. This mechanism is different from many current treatments that do not specifically target blood flow enhancement. Additionally, sildenafil is being tested in various doses, which might help researchers identify the most effective and safe dosage for improving outcomes in traumatic brain injury patients.

What evidence suggests that this trial's treatments could be effective for traumatic brain injury?

Research has shown that sildenafil can aid recovery after a traumatic brain injury (TBI). Studies have found that sildenafil increases blood flow in the brain and enhances the responsiveness of the brain's blood vessels, which is crucial for healing. In one study, sildenafil reduced symptoms after a concussion, helping patients feel better. Another study found that a single dose of sildenafil improved how the brain's blood vessels reacted in TBI patients, suggesting it aids in brain healing. Overall, these findings suggest that sildenafil may help recovery from TBI by improving blood flow and reducing symptoms. This trial will evaluate different dosages of sildenafil—low, medium, and high—to determine their effectiveness in aiding recovery from TBI. ^{1 2 6 7 8}

Who Is on the Research Team?

Ramon Diaz-Arrastia, MD, PhD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10684467/

Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for ... Our pilot study also demonstrated that daily use of low-dose sildenafil was well tolerated in chronic moderate-to-severe TBI (n = 22).

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01762475

NCT01762475 | Sildenafil for Cerebrovascular Dysfunction ... Treatment with sildenafil for 8 weeks (25 mg orally twice daily) reduces the prevalence of post-concussive symptoms, compared to placebo treatment. 24 months.

3. cdmrp.health.mil cdmrp.health.mil/tbiphrp/research_highlights/23Diaz-Arrastia_highlight

Traumatic Brain Injury and Psychological Health Upon completion of the clinical trial, the researchers found that a single treatment with sildenafil increased CVR in TBI patients (Figure 1).

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03598140

NCT03598140 | Sildenafil Treatment for Mild TBI The goal of the proposed research is to test the efficacy of Viagra® (sildenafil) at normalizing CBF and improving cognitive outcomes in people that have ...

5. apps.dtic.mil apps.dtic.mil/sti/trecms/pdf/AD1219036.pdf

Phase 2 Randomized Controlled Trial of Sildenafil Citrate for ... The failure of multiple Phase III clinical trials of therapies known to be effective in animals has forced a re-evaluation of clinical studies in traumatic ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9127063/

The Role of Sildenafil in Treating Brain Injuries in Adults and ... This study is a comprehensive review of the demonstrated effects of sildenafil on the brain with respect to its function, extent of injury, ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05782244?tab=table

Sildenafil for Microvasculopathy in Chronic TBI 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 ...

8. trialx.com trialx.com/clinical-trials/listings/288668/sildenafil-for-microvasculopathy-in-chronic-tbi/

Sildenafil for Microvasculopathy in Chronic TBI The investigators will also test the safety and tolerability of the same dose ranges of chronic (4-week) thrice daily sildenafil or placebo ...