Combination Therapy + BPA for Thromboembolic Pulmonary Hypertension

(EPIPHANY Trial)

Overseen By David Ptashnik, MS

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Dr Sudarshan Rajagopal

Disqualifiers: Heart disease, Sarcoidosis, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

15 Participants Needed

Trial Summary

What is the purpose of this trial?

The main goal of this study is to determine the effects of combination medical therapy (Riociguat and Macitentan) and balloon pulmonary angioplasty (BPA) on hemodynamics and right ventricular (RV) function (including advanced assessments of RV-pulmonary artery (PA) coupling from invasive hemodynamics) in participants with inoperable or post-PTE residual CTEPH.

Will I have to stop taking my current medications?

The trial requires participants to be treatment-naïve, meaning you cannot be on any specific medications for CTEPH or pulmonary arterial hypertension before starting the study. If you are currently taking such medications, you would need to stop them before participating.

What data supports the effectiveness of the treatment Balloon Pulmonary Angioplasty, Macitentan Tablets, and Riociguat for Thromboembolic Pulmonary Hypertension?

Research shows that the combination of macitentan and riociguat improved exercise capacity and reduced symptoms in patients with pulmonary arterial hypertension (a type of high blood pressure affecting the lungs), suggesting potential benefits for similar conditions. ^{1 2 3 4 5}

Is the combination therapy of macitentan and riociguat safe for humans?

The combination of macitentan and riociguat has been studied in patients with pulmonary arterial hypertension and showed no unexpected or serious side effects. Macitentan alone also has a favorable safety profile, with no significant increase in liver damage or swelling, although it may cause anemia (low red blood cell count). ^{1 2 4 5 6}

How does the combination therapy with macitentan and riociguat differ from other treatments for thromboembolic pulmonary hypertension?

This combination therapy is unique because it uses two drugs, macitentan and riociguat, which target different pathways involved in pulmonary hypertension, potentially offering a more comprehensive approach to treatment. Macitentan blocks endothelin receptors, while riociguat enhances the nitric oxide pathway, which may improve blood flow and reduce blood pressure in the lungs more effectively than single-drug treatments. ^{1 2 4 7 8}

Research Team

Sudarshan Rajagopal, MD, PhD

Principal Investigator

Duke Health System

Eligibility Criteria

This trial is for adults over 18 with CTEPH who can't have surgery, haven't started treatment, and are eligible for balloon pulmonary angioplasty (BPA). They must be able to consent and follow the study plan. People with contraindications to the drugs being tested, severe liver disease, heart conditions, active cancer or sickle cell anemia cannot participate.

Inclusion Criteria

I am not eligible for pulmonary thromboendarterectomy.

I am 18 years old or older.

Willing and able to give informed consent and adhere to visit/protocol schedules (Consent must be given before any study procedures are performed)

Exclusion Criteria

I cannot take riociguat or macitentan due to adverse reactions.

I have severe liver disease.

My cancer is currently active.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Combination Medical Therapy

Participants receive combination medical therapy with Riociguat and Macitentan

up to 6 months

Regular visits for monitoring

Balloon Pulmonary Angioplasty (BPA)

Participants undergo balloon pulmonary angioplasty to improve hemodynamics and RV-PA coupling

up to 6 months

Regular visits for procedure and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Balloon Pulmonary Angioplasty
• Macitentan Tablets
• Riociguat

Trial Overview The study tests how a combination of Macitentan tablets and Riociguat followed by BPA affects blood flow dynamics and right heart function in patients with CTEPH that's not suitable for surgery. It aims to see if this approach improves the coupling between the right ventricle and pulmonary artery.

Participant Groups

Group I: participants with inoperable CTEPH Active Control 3 Interventions

subject with inoperable Chronic thromboembolic Pulmonary Hypertension

Group II: post PTE residual CTEPH Active Control 3 Interventions

Subject with post pulmonary endarterectomy (PTE) residual Chronic Thromboembolic Pulmonary Hypertension

Who Is Running the Clinical Trial?

Dr Sudarshan Rajagopal

Lead Sponsor

Trials

1

Recruited

20+

Janssen Pharmaceutica N.V., Belgium

Industry Sponsor

Trials

84

Recruited

31,600+

Joaquin Duato

Janssen Pharmaceutica N.V., Belgium

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Biljana Naumovic

Janssen Pharmaceutica N.V., Belgium

Chief Medical Officer since 2019

MD from Belgrade University Medical School, Executive Education from London Business School

Actelion

Industry Sponsor

Trials

192

Recruited

35,500+

Jean-Paul Clozel

Actelion

Chief Executive Officer since 1997

MD from University of Basel

Martine Clozel

Actelion

Chief Medical Officer since 1997

MD from University of Geneva

Findings from Research

In a study of 15 newly diagnosed pulmonary arterial hypertension (PAH) patients, the combination therapy of macitentan and riociguat significantly improved exercise capacity, as shown by an increase in the 6-minute walk distance from 281.6 m at baseline to 315.7 m at 4 months and 313.9 m at 12 months (P < 0.05).

The therapy also led to significant improvements in hemodynamic parameters, including a decrease in pulmonary vascular resistance and mean pulmonary artery pressure, with a transplant-free survival rate of 85% over 36 months, indicating the treatment's potential efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and hemodynamic benefit of macitentan and riociguat upfront combination in patients with pulmonary arterial hypertension. Sulica, R., Sangli, S., Chakravarti, A., et al.[2020]

In a study of 26 patients with pulmonary arterial hypertension (PAH), triple oral combination therapy using macitentan, riociguat, and selexipag significantly improved key clinical measures, including pulmonary arterial pressure and cardiac output, over a median observation period of 441 days.

The therapy was well tolerated, with a high survival rate of 93.3% and a prostacyclin infusion-free rate of 74.6% at 3 years, suggesting it is particularly effective for low/intermediate-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension. Momoi, M., Hiraide, T., Shinya, Y., et al.[2021]

Macitentan, a dual endothelin receptor antagonist, significantly reduces the risk of morbidity and mortality in patients with pulmonary arterial hypertension (PAH) by 45% compared to placebo, particularly benefiting those in WHO functional class II and III.

In the largest and longest trial for PAH to date, macitentan improved patients' exercise capacity, quality of life, and cardiopulmonary hemodynamics, while also demonstrating a favorable safety profile, marking a shift towards long-term outcome-oriented therapy in PAH management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of macitentan for the treatment of pulmonary arterial hypertension. Selej, M., Romero, AJ., Channick, RN., et al.[2016]

In a study involving 14 healthy male subjects, macitentan did not alter the pharmacokinetics or pharmacodynamics of warfarin, indicating that the two medications can be safely used together without requiring dose adjustments.

The study found that plasma concentrations of warfarin remained consistent whether macitentan was administered or not, suggesting no significant drug interactions between these two treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Sidharta, PN., Dietrich, H., Dingemanse, J.[2021]

In a clinical practice setting involving 13 patients with pulmonary arterial hypertension (PAH), 12 months of treatment with macitentan led to significant improvements in functional class and 6-minute walk distance for all patients.

Macitentan treatment also resulted in decreased NT-proBNP levels and improved cardiac imaging parameters, with no hospitalizations or serious adverse events reported during the study period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Macitentan in daily clinical practice: A single centre, 1-year experience. Cadenas-Menéndez, S., Álvarez-Vega, P., Martín-Moreiras, J., et al.[2019]

Macitentan is an effective treatment for symptomatic pulmonary arterial hypertension, showing significant improvements in patients' functional class, exercise tolerance, and hemodynamic parameters in the pivotal SERAPHIN study.

It has a favorable safety profile, with no increased risk of liver damage or swelling, although it may cause significant anemia; it also allows for once-daily dosing due to its long duration of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Macitentan for the treatment of pulmonary arterial hypertension. Kholdani, CA., Fares, WH., Trow, TK.[2018]

Macitentan, at a dose of 10 mg, does not alter the pharmacokinetics of the drugs rosuvastatin and riociguat, indicating that it can be safely used in combination with these medications without affecting their effectiveness.

The studies confirmed that the safety profiles of macitentan, rosuvastatin, and riociguat remained consistent, suggesting that these drugs can be administered together without significant adverse interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects. Csonka, D., Bruderer, S., Schultz, A., et al.[2020]

Macitentan is a potent dual receptor antagonist approved for treating pulmonary arterial hypertension (PAH), showing long-term benefits in reducing morbidity and mortality associated with the disease.

In clinical studies, macitentan improved hemodynamics, exercise capacity, and functional class in patients with PAH, with common side effects including nasopharyngitis, bronchitis, and a higher risk of anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Macitentan in the treatment of pulmonary arterial hypertension. Zebadúa, R., Hernández-Pérez, AP., García, A., et al.[2021]

References

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

Clinical and hemodynamic benefit of macitentan and riociguat upfront combination in patients with pulmonary arterial hypertension. [2020]

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

Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension. [2021]

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

Development of macitentan for the treatment of pulmonary arterial hypertension. [2016]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. [2021]

5. Spain pubmed.ncbi.nlm.nih.gov

Macitentan in daily clinical practice: A single centre, 1-year experience. [2019]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Macitentan for the treatment of pulmonary arterial hypertension. [2018]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Macitentan in the treatment of pulmonary arterial hypertension. [2021]