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

Trial Summary

What is the purpose of this trial?

This is a Phase II randomized, double-blind, placebo-controlled trial of sildenafil in men and women with Scleroderma with mildly elevated pulmonary pressures (SSc-MEP) to determine whether sildenafil may be an effective treatment for SSc-MEP.

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.

What data supports the effectiveness of the drug sildenafil for treating scleroderma?

Research shows that sildenafil, a type of drug called a phosphodiesterase inhibitor, is effective for healing digital ulcers (painful sores on fingers or toes) in people with systemic sclerosis, a form of scleroderma. This is supported by studies like the SEDUCE study, which specifically assessed sildenafil's impact on these ulcers. ^{1 2 3 4 5}

Is sildenafil safe for treating scleroderma-related conditions?

Sildenafil has been used safely in patients with scleroderma for conditions like severe pulmonary hypertension and nonhealing ulcers, showing significant improvement without reported safety issues in the provided studies. ^{6 7 8 9 10}

How does the drug sildenafil differ from other treatments for scleroderma?

Sildenafil is unique for scleroderma treatment because it increases nitric oxide levels, which helps dilate blood vessels and improve blood flow, potentially aiding in the healing of ulcers and reducing symptoms of Raynaud's phenomenon. Unlike other treatments that primarily target the immune system, sildenafil focuses on improving vascular health, making it a novel option for managing scleroderma-related vascular issues. ^{7 8 11 12 13}

Research Team

Stephen Mathai, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

References

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

Differing commissioning arrangements may contribute to geographic variation in clinical management of digital ulcers in systemic sclerosis. [2023]

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

Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study. [2022]

3. Canada 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. [2022]

4. United States 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. [2022]

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

Outcome measurement in scleroderma clinical trials. [2019]

6. Japan pubmed.ncbi.nlm.nih.gov

Treatment of severe pulmonary hypertension secondary to scleroderma: a three-drug approach. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

[Fast and efficient healing of scleroderma-associated acral ulcers with sildenafil]. [2022]

8. Canada pubmed.ncbi.nlm.nih.gov

Severe refractory fingertip ulcerations in a patient with scleroderma: successful treatment with sildenafil. [2015]

9. Canada 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. [2015]

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

Changes in gene expression profiles in patients with pulmonary arterial hypertension associated with scleroderma treated with tadalafil. [2018]

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

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

12. Switzerland pubmed.ncbi.nlm.nih.gov

Systemic sclerosis - a systematic overview: part 2 - immunosuppression, treatment of SSc-associated vasculopathy, and treatment of pulmonary arterial hypertension. [2014]

13. England 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. [2022]