Combination Therapy + BPA for Thromboembolic Pulmonary Hypertension

(EPIPHANY Trial)

Overseen By Claudia Salazar

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of medications, Riociguat and Macitentan (both oral), along with a procedure called balloon pulmonary angioplasty (BPA). The aim is to evaluate their effectiveness for individuals with chronic thromboembolic pulmonary hypertension (CTEPH), a specific type of high blood pressure in the lungs. The researchers seek to understand how these treatments impact heart function and blood flow in participants who cannot undergo surgery or continue to experience issues post-surgery. The trial is recruiting individuals diagnosed with CTEPH who cannot have a certain surgery and have not yet started specific treatments for their condition. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that both macitentan and riociguat have been studied for safety in treating chronic thromboembolic pulmonary hypertension (CTEPH).

Long-term studies indicate that macitentan is safe and effective for patients who cannot undergo surgery for CTEPH. These studies found no unexpected safety issues. Patients using macitentan alone or with other treatments improved over two years.

Riociguat also maintains a strong safety record. Studies have found it to be well-tolerated and effective in enhancing exercise capacity and function in people with CTEPH. Reports confirm that its safety in everyday use aligns with existing knowledge about the drug.

Overall, both treatments have demonstrated safety for people with CTEPH, providing reassurance for those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Macitentan and Riociguat for treating chronic thromboembolic pulmonary hypertension (CTEPH) because these drugs work synergistically to target different pathways involved in this condition. Unlike standard treatments, which often involve surgery or single-drug therapies, Macitentan blocks the endothelin receptor, reducing blood vessel constriction, while Riociguat enhances the nitric oxide pathway, improving blood flow. This dual approach not only offers a non-surgical option for patients with inoperable CTEPH but also shows promise for those with residual hypertension after surgery, potentially leading to better outcomes and improved quality of life.

What evidence suggests that this trial's treatments could be effective for thromboembolic pulmonary hypertension?

In this trial, participants will receive either macitentan or riociguat as part of the treatment for chronic thromboembolic pulmonary hypertension (CTEPH). Previous studies have shown that macitentan significantly improves blood flow in the lungs of patients with inoperable CTEPH, reducing hospital visits related to the condition. Research indicates that riociguat enhances exercise capacity and improves blood flow in the lungs for patients with CTEPH. These findings suggest that both macitentan and riociguat effectively manage CTEPH, improving lung function and overall physical ability in those affected. ^{2 3 6 7 8}

Who Is on the Research Team?

Sudarshan Rajagopal, MD, PhD

Principal Investigator

Duke Health System

Are You a Good Fit for This Trial?

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.

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

I have been diagnosed with chronic thromboembolic pulmonary hypertension.

Exclusion Criteria

I cannot take riociguat or macitentan due to adverse reactions.

I have severe liver disease.

My cancer is currently active.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Dr. Jijo James, MD

Janssen Pharmaceutica N.V., Belgium

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

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

Published Research Related to This Trial

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]

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, 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 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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39520648/

Long-Term Safety and Efficacy of Macitentan in Inoperable ... These analyses provide long-term safety/efficacy data in patients with inoperable CTEPH treated with macitentan. No unexpected safety findings occurred.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2213260024000274

Macitentan for the treatment of inoperable chronic ... In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated.

3. resmedjournal.com resmedjournal.com/article/S0954-6111(25)00174-X/fulltext

A real-world comparative effectiveness analysis of ... Macitentan was associated with a significantly reduced risk of PAH-related and all-cause hospitalization, with lower ICU healthcare resource utilization, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04271475

NCT04271475 | A Study to Evaluate Efficacy and Safety of ... This study will assess the effect of macitentan 75 mg on exercise capacity in CTEPH. The total duration of the study is approximately 6 years.

5. thelancet.com thelancet.com/journals/lanres/article/PIIS2213-2600(24)00027-4/abstract

Macitentan for the treatment of inoperable chronic ... Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double- ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11861443/

Long-Term Safety and Efficacy of Macitentan in Inoperable ... These analyses of MERIT-1 and MERIT-2 provide long-term safety and efficacy data in patients with inoperable CTEPH treated with macitentan 10 mg.

7. sciencedirect.com sciencedirect.com/science/article/pii/S0954611120301062

Long-term real world clinical outcomes of macitentan ... Macitentan mono- and combination therapy in non-operated CTEPH and residual PH is safe and improves clinical outcomes till 2-year follow-up.

8. jnjmedicalconnect.com jnjmedicalconnect.com/products/opsumit/medical-content/efficacy-and-safety-of-opsumit-in-patients-with-chronic-thromboembolic-pulmonary-hypertension

Efficacy and Safety of OPSUMIT in Patients With Chronic ... A summary of the efficacy and safety of OPSUMIT® (macitentan) in patients with chronic thromboembolic pulmonary hypertension.