Sildenafil for Scleroderma

(SEPVADIS Trial)

Recruiting at 1 trial location

Overseen By Renee Ofori

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Johns Hopkins University

Must not be taking: Nitrates, PAH therapy

Disqualifiers: WHO Class IV, Renal failure, others

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

Compensation: Varies

Number of Visits: 4

Duration: 12 months

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether sildenafil, a drug commonly used for other conditions, can help people with scleroderma who have slightly high blood pressure in their lungs. Participants will receive either sildenafil or a placebo (a sugar pill) to determine if sildenafil makes a difference. Those who might benefit from joining this trial include individuals diagnosed with scleroderma and mildly elevated pulmonary pressures. As a Phase 2 trial, this research measures how well sildenafil works in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Do I need to stop my current medications to join the trial?

The trial requires that you have not used certain medications for Pulmonary Arterial Hypertension (PAH) in the past 3 months and that you are not currently using nitrates. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

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

Research has shown that sildenafil, commonly used for erectile dysfunction, has been studied for safety in people with systemic sclerosis (SSc). One study involved 19 patients with this condition who took sildenafil for up to six months, showing promising results without major safety concerns.

Sildenafil can cause common side effects such as indigestion, headaches, vision problems, flushing, muscle pain, and diarrhea. However, these side effects are usually manageable. Another study found that sildenafil might help improve heart function in people with systemic sclerosis, indicating a positive sign for its safety and effectiveness.

While these studies provide some insight into the safety of sildenafil for systemic sclerosis, it's important to note that this trial is still in an early phase. This means the treatment’s safety and effectiveness are still under close examination. Overall, existing research suggests that sildenafil is fairly well-tolerated, but ongoing trials will provide more detailed information. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Scleroderma?

Unlike standard treatments for scleroderma, which often focus on managing symptoms with medications like immunosuppressants or anti-fibrotic agents, sildenafil offers a novel approach by targeting blood flow. Sildenafil, commonly known for treating erectile dysfunction, works by dilating blood vessels, which could improve circulation in patients with scleroderma. Researchers are excited because this mechanism may address one of the underlying issues in scleroderma, potentially reducing complications related to poor blood circulation. This could provide a complementary option to existing therapies, offering hope for improved quality of life for patients.

What evidence suggests that sildenafil might be an effective treatment for Scleroderma?

Research shows that sildenafil, initially used for erectile dysfunction, might benefit people with scleroderma who have slightly elevated blood pressure in their lungs. Studies have found that sildenafil can heal painful sores on fingers and toes in individuals with systemic sclerosis, a condition related to scleroderma. In this trial, participants will receive either sildenafil or a placebo. Specifically, patients taking sildenafil had fewer sores than those taking a placebo. Additionally, sildenafil has been linked to improved heart function in people with systemic sclerosis, showing fewer issues like heart stiffness. Overall, these findings suggest that sildenafil could effectively treat some symptoms of scleroderma. ^{1 2 6 7 8}

Who Is on the Research Team?

Stephen Mathai, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for men and women with Scleroderma who have mildly elevated pulmonary pressures. Participants must meet specific criteria including a diagnosis of SSc, the ability to perform certain lung function tests, and not be severely ill or hospitalized. They should not be on other investigational drugs or PAH therapy recently, nor have significant heart issues or untreated sleep apnea.

Inclusion Criteria

My lung function tests show I have more than half the normal breathing capacity.

My scans show no signs of chronic blood clots.

I can walk for six minutes without difficulty.

Exclusion Criteria

My kidney function is impaired with high creatinine levels.

I am unable to carry out any physical activity without discomfort.

I have a heart condition affecting the left side or my heart's pumping ability is reduced.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sildenafil or placebo by mouth three times each day

12 months

Regular visits for assessments at baseline, 4 months, and 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term safety monitoring

Ongoing assessment of safety profile through adverse event monitoring

Up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Sildenafil

Trial Overview The study is testing sildenafil against a placebo in patients with Scleroderma to see if it can effectively treat mildly elevated pulmonary pressures. It's a Phase II trial where participants are randomly assigned to either the medication or an inactive substance without knowing which one they receive.

How Is the Trial Designed?

Group I: Sildenafil Experimental Treatment 1 Intervention

Sildenafil 20 mg by mouth three(3) times each day

Group II: Placebo Placebo Group 1 Intervention

Placebo by mouth three(3) times each day

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Louisiana State University Health Sciences Center in New Orleans

Collaborator

Trials

123

Recruited

42,400+

Published Research Related to This Trial

In a case of scleroderma with severe pulmonary hypertension, a combination of three drugs—bosentan, iloprost, and sildenafil—led to significant improvements in both clinical symptoms and pulmonary blood flow.

This approach suggests that using multiple pulmonary vasodilators with different mechanisms can be effective for patients who do not respond to standard treatments for severe pulmonary hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of severe pulmonary hypertension secondary to scleroderma: a three-drug approach. Catapano-Minotti, G., Corsonello, A., Guadalupi, G., et al.[2019]

Sildenafil, a phosphodiesterase-5 inhibitor, was effective in treating acral ulcers in a 35-year-old male patient with progressive systemic sclerosis, leading to complete healing of the ulcers within five weeks.

The patient also experienced significant improvements in symptoms, including reduced dyspnea and increased walking distance, within just one week of starting sildenafil treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Fast and efficient healing of scleroderma-associated acral ulcers with sildenafil]. Friedrichson, E., Rehberger, P., Fuhrmann, JT., et al.[2022]

A patient with limited cutaneous systemic sclerosis experienced severe nonhealing finger ulcers, which did not improve with standard treatments.

Oral sildenafil, a medication that increases nitric oxide levels, led to significant improvement in the patient's condition, suggesting its potential as an effective therapy for vascular issues in scleroderma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe refractory fingertip ulcerations in a patient with scleroderma: successful treatment with sildenafil. Colglazier, CL., Sutej, PG., O'Rourke, KS.[2015]

Experts believe that warfarin may have a minimal impact on 3-year survival rates in patients with scleroderma-associated pulmonary arterial hypertension (SSc-PAH) and idiopathic pulmonary arterial hypertension (IPAH), with survival probabilities of 56% and 76% respectively when treated with warfarin.

There is significant uncertainty among experts regarding warfarin's effects, with some believing it could worsen survival by 7% while others think it could improve it by 13%, highlighting the need for further clinical trials to clarify its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of warfarin on survival in scleroderma-associated pulmonary arterial hypertension (SSc-PAH) and idiopathic PAH. Belief elicitation for Bayesian priors. Johnson, SR., Granton, JT., Tomlinson, GA., et al.[2015]

In a pilot study involving 10 scleroderma patients with pulmonary arterial hypertension (SSc-PAH), 16 weeks of tadalafil treatment led to significant changes in gene expression related to immune response and vascular function, indicating a potential mechanism of action for the drug.

Patients who showed improvement with tadalafil had specific up-regulation of genes associated with potassium channels and innate immunity, while those who worsened exhibited changes in Golgi-related gene sets, suggesting that gene expression profiles could help predict treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in gene expression profiles in patients with pulmonary arterial hypertension associated with scleroderma treated with tadalafil. Cheong, FY., Gower, AC., Farber, HW.[2018]

Phosphodiesterase inhibitors like sildenafil and endothelin receptor antagonists such as bosentan are effective treatments for digital ulcer disease in systemic sclerosis, as supported by international guidelines.

A multicentre evaluation revealed that the use of these medications varies geographically in the UK, with increased sildenafil use in SW England post-2015, while bosentan use remains lower in Wales due to differing commissioning practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differing commissioning arrangements may contribute to geographic variation in clinical management of digital ulcers in systemic sclerosis. Reilly, E., Alshakh, R., Beynon, C., et al.[2023]

In a randomized, placebo-controlled study involving 83 patients with systemic sclerosis, sildenafil showed a significant reduction in the number of digital ulcers (DUs) at weeks 8 and 12 compared to placebo, indicating its potential benefit in healing.

Although the primary endpoint of time to healing was not statistically significant in the intention-to-treat analysis, the per protocol analysis suggested a trend towards improved healing rates with sildenafil, highlighting its efficacy in managing DUs in systemic sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study. Hachulla, E., Hatron, PY., Carpentier, P., et al.[2022]

The modified Localized Scleroderma Skin Severity Index (mLoSSI) and Physician Global Assessment of disease activity (PhysGA-A) demonstrated excellent reliability and validity for assessing disease severity in localized scleroderma, making them effective tools for clinical practice.

Both mLoSSI and PhysGA-A were sensitive to changes in disease severity over time, indicating their usefulness in monitoring treatment effects and supporting their inclusion in clinical trials for localized scleroderma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The localized scleroderma skin severity index and physician global assessment of disease activity: a work in progress toward development of localized scleroderma outcome measures. Arkachaisri, T., Vilaiyuk, S., Li, S., et al.[2022]

A 48-year-old woman with systemic sclerosis and severe limb claudication showed significant improvement in her maximum walking distance (MWD) from 118 m to 1576 m after receiving combined therapy with Sildenafil and Bosentan.

The combination therapy not only alleviated her walking pain but also improved her quality of life, suggesting a safe and effective treatment approach for patients with systemic sclerosis and peripheral artery disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improvement of peripheral artery disease with Sildenafil and Bosentan combined therapy in a patient with limited cutaneous systemic sclerosis: A case report. Omarjee, L., Fontaine, C., Mahe, G., et al.[2022]

A review of 27 controlled intervention studies in scleroderma found that while some outcome measures, particularly skin involvement, showed statistical differences in response to treatment, many measures failed to detect significant changes, indicating a need for better assessment tools.

The study highlights the importance of developing standardized and sensitive outcome measures for future clinical trials in scleroderma to accurately differentiate between true therapeutic efficacy and limitations in current measurement methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome measurement in scleroderma clinical trials. Pope, JE., Bellamy, N.[2019]

Current treatments for scleroderma primarily focus on managing immune response and vascular issues, with recent trials showing that cyclophosphamide is effective for interstitial lung disease and endothelin receptor antagonists, sildenafil, and prostacyclins are beneficial for vascular complications like Raynaud's phenomenon.

Despite the lack of standardized treatment guidelines, various therapies have shown modest benefits, including alpha1-antagonists and calcium channel blockers for Raynaud's, while methotrexate has only a limited effect on skin disease associated with scleroderma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current drug therapy for scleroderma and secondary Raynaud's phenomenon: evidence-based review. Henness, S., Wigley, FM.[2007]

Immunosuppressant therapy in systemic sclerosis (SSc) should be approached cautiously due to its generally weaker response compared to other connective tissue disorders, and steroid doses should be limited to prevent renal crises.

Prostanoids like iloprost are effective for severe Raynaud's phenomenon and digital ulcers, while combination therapies involving phosphodiesterase inhibitors and endothelin receptor antagonists are being evaluated for better outcomes in treating these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic sclerosis - a systematic overview: part 2 - immunosuppression, treatment of SSc-associated vasculopathy, and treatment of pulmonary arterial hypertension. Opitz, C., Klein-Weigel, PF., Riemekasten, G.[2014]

In a 24-week randomized trial involving 29 patients with systemic sclerosis, those treated with low-dose methotrexate (MTX) showed a significantly higher favorable response rate (53%) compared to the placebo group (10%), indicating its potential efficacy in treating this condition.

After an additional 24 weeks of treatment, 68% of patients who received MTX from the start demonstrated significant improvements in skin score, general well-being, and other health measures, suggesting that MTX can lead to meaningful clinical benefits for patients with active systemic sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. van den Hoogen, FH., Boerbooms, AM., Swaak, AJ., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3216380/

PDE-5 Inhibitors in Scleroderma Raynaud Phenomenon ... The study reported no adverse events, aside from a mild decrease in the systolic and diastolic blood pressure (P < 0.05) in the patients exposed to sildenafil [ ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2938897/

Effect of sildenafil on digital ulcers in systemic sclerosis A total of 19 patients with systemic sclerosis (SSc) were treated with maximally tolerated sildenafil doses up to 6 months. Primary outcome was the healing of ...

3. ard.bmj.com ard.bmj.com/content/75/6/1009

Efficacy of sildenafil on ischaemic digital ulcer healing in ... We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01347008?term=AREA%5BConditionSearch%5D(%22Scleroderma,%20Limited%22)&rank=6&tab=results

Study Results | Effect of Sildenafil on the Microcirculatory ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a ...

5. rmdopen.bmj.com rmdopen.bmj.com/content/10/4/e004918

Vasodilator drugs and heart-related outcomes in systemic ... The study found that sildenafil use in SSc patients was associated with a reduced incidence of diastolic dysfunction and altered ejection ...

6. sclerodermanews.com sclerodermanews.com/sildenafil/

Sildenafil Common side effects of sildenafil include indigestion, headaches, vision problems, and flushing. Others include muscle pain, diarrhea ...

7. clinicaltrials.gov clinicaltrials.gov/search?cond=%22Diffuse%20Scleroderma%22&intr=%22sildenafil%20citrate%22&viewType=Table&rank=7

"Diffuse Scleroderma", "sildenafil citrate" | Card Results A phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers, and the goal is to ...

8. scholar.usuhs.edu scholar.usuhs.edu/en/publications/three-year-update-of-sildenafil-citrate-viagra-efficacy-and-safet/

Three-year update of sildenafil citrate (Viagra®) efficacy ... Significant improvements in erectile function have been demonstrated in double-blind, placebo-controlled trials in patients with ED and underlying diabetes, ...