What side effects are associated with this type of intervention?

Common treatments for Pulmonary Arterial Hypertension (PAH) include Endothelin Receptor Antagonists (ERAs) like macitentan, phosphodiesterase-5 inhibitors (PDE5Is) such as sildenafil and tadalafil, and prostacyclin analogues like epoprostenol and treprostinil. ERAs, including macitentan, can cause hepatotoxicity and peripheral edema. PDE5Is are associated with side effects like headache, flushing, dyspepsia, and visual disturbances. Prostacyclin analogues often cause jaw pain, nausea, diarrhea, and flushing. These treatments aim to improve hemodynamic parameters, exercise capacity, and quality of life in PAH patients, but they come with a range of potential adverse effects that need to be managed under medical supervision.

What prior FDA approvals exist?

The FDA has approved several drugs for the treatment of Pulmonary Arterial Hypertension (PAH), particularly focusing on Endothelin Receptor Antagonists (ERAs) similar to macitentan. Notable ERAs include bosentan and ambrisentan, which have been shown to improve exercise capacity, delay disease progression, and enhance quality of life in PAH patients. Additionally, other drug classes such as Phosphodiesterase-5 Inhibitors (e.g., sildenafil and tadalafil) and Prostacyclin Analogues (e.g., epoprostenol and treprostinil) have also received FDA approval for PAH treatment, offering various administration routes and mechanisms to manage the disease effectively.

What other types of research exist?

Promising alternatives to Macitentan for PAH treatment include: <ol> <li>Riociguat: A soluble guanylate cyclase (sGC) stimulator that has shown efficacy in improving exercise capacity and delaying clinical worsening.</li> <li>Selexipag: An oral prostacyclin receptor agonist that targets the prostacyclin pathway, shown to improve long-term outcomes in PAH patients.</li> <li>Oral Treprostinil: A prostacyclin analog that has demonstrated benefits in exercise capacity and symptoms when added to background therapy.</li> <li>Sildenafil and Tadalafil: Phosphodiesterase-5 inhibitors (PDE5Is) that improve hemodynamics and exercise capacity in PAH patients.</li> </ol>

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Endothelin Receptor Antagonist

High-Dose Macitentan for PAH (UNISUS Trial)

Q: What is the mechanism of action of this treatment?

The most common treatments for Pulmonary Arterial Hypertension (PAH) include Endothelin Receptor Antagonists (ERAs) like Macitentan, Phosphodiesterase-5 Inhibitors (PDE5Is) such as Sildenafil and Tadalafil, and Prostacyclin Analogues. ERAs work by blocking endothelin-1, a potent vasoconstrictor, thereby reducing blood vessel constriction and lowering pulmonary blood pressure. PDE5Is enhance the effects of nitric oxide, leading to vasodilation and improved blood flow in the lungs. Prostacyclin Analogues mimic the effects of prostacyclin, a natural vasodilator, and inhibit platelet aggregation. These mechanisms are crucial for PAH patients as they help to alleviate symptoms, improve exercise capacity, and slow disease progression by targeting the underlying pathophysiological processes of the disease.

Phase 3

Waitlist Available

Research Sponsored by Actelion

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Able to perform the 6-minute walking test (6MWT) with specific distance criteria at screening

Symptomatic Pulmonary Arterial Hypertension (PAH) in World Health Organization Functional Class (WHO FC) II, III, or IV

Must not have

Known moderate to severe hepatic impairment

Presence of moderate or severe obstructive lung disease

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 6 years

Awards & highlights

Pivotal Trial

Summary

This trial is testing if a higher dose of macitentan can better help patients with pulmonary arterial hypertension by improving blood flow in their lungs. Macitentan has shown promise in helping patients by slowing down the disease and improving their health.

Who is the study for?

Adults with symptomatic Pulmonary Arterial Hypertension (PAH) in various severity classes, confirmed by specific heart and lung pressure measurements. Eligible participants include those with PAH due to different causes such as genetic factors, drug use, or associated diseases like HIV. They must be able to perform a walking test and not have severe liver issues, certain blood disorders, or significant risk factors for heart failure.

What is being tested?

The trial is testing the effectiveness of a higher dose of Macitentan (75 mg) compared to the standard dose (10 mg) in delaying health deterioration or death in PAH patients. Participants will randomly receive either the high dose, standard dose, an intermediate dose (37.5 mg), or a placebo.

What are the potential side effects?

Macitentan may cause side effects such as liver problems; low red blood cell counts leading to fatigue; respiratory infections; headache; dizziness; gastrointestinal symptoms like nausea and diarrhea; skin rash; and anemia.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I can complete a 6-minute walking test.

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I have symptoms of severe lung blood pressure in stages II, III, or IV.

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My PAH is related to a specific cause like a genetic condition, drug use, or another disease.

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My PAH is related to a specific cause like a genetic condition, drug use, or another disease.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have a known liver condition that is moderate to severe.

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I have severe breathing problems due to lung blockage.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 6 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 6 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 6 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Double-blind Treatment Period: Time to First Clinical Events Committee (CEC)-adjudicated Morbidity or Mortality (M/M) Events

Secondary study objectives

Double-blind Treatment Period: Change From Baseline to Week 24 in 6MWD

Therapeutic procedure

Double-blind Treatment Period: Change From Baseline to Week 24 in PAH Symptoms Based on PAH-SYMPACT Questionnaire- Cardiovascular Symptom Domain Score

+3 more

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: Macitentan 75 mg + PlaceboExperimental Treatment4 Interventions

Run-in period:Participants who are either ERA-naive or who are receiving a daily dose of macitentan or ambrisentan \<10 mg, or a daily dose of bosentan \<250 mg, will enter 4-week open-label run-in period with macitentan 10 mg prior to randomization. ERA-pre-treated patients will bypass the run-in period and will be randomized to either macitentan 75 mg or macitentan 10 mg directly.DBT Period: participants will receive macitentan 37.5 mg orally for 4 weeks and macitentan 75 mg thereafter up to End of DBT. To maintain the blind, participants will receive macitentan 10 mg-matching placebo up to End of DBT.Treatment Extension Period: After EDBT, participants will continue to receive macitentan 75 mg orally for 2 years. To maintain the blind, participants will receive macitentan 37.5 mg-matching placebo during the 4-week up-titration period.

Group II: Macitentan 10 milligrams (mg) + PlaceboActive Control4 Interventions

Run-in period:Participants who are either endothelin receptor antagonist (ERA)-naïve or who are receiving daily dose of macitentan or ambrisentan less (\<) 10 milligrams (mg), or daily dose of bosentan \<250 mg, will enter 4-week open-label run-in period with macitentan 10 mg prior to randomization. ERA-pre-treated participants will bypass run-in period and will be randomized to either macitentan 75 mg or macitentan 10 mg directly.Double-blind Treatment (DBT) Period:Participants will receive macitentan 10 mg orally up to End of DBT.To maintain blind, participants will receive macitentan 37.5 mg-matching placebo for 4 weeks and macitentan 75 mg-matching placebo thereafter up to DBT.Treatment Extension Period:After EDBT, participants will receive macitentan 37.5 mg once a day (qd) orally for 4 weeks, prior to receiving open-label macitentan 75 mg qd orally for 2 years. To maintain blind, participants will receive macitentan 75 mg-matching placebo during 4-week uptitration.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Macitentan 10 mg

2021

Completed Phase 3

~680

Placebo

1995

Completed Phase 3

~2670

0 / 6Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Pulmonary Arterial Hypertension (PAH) include Endothelin Receptor Antagonists (ERAs) like Macitentan, Phosphodiesterase-5 Inhibitors (PDE5Is) such as Sildenafil and Tadalafil, and Prostacyclin Analogues. ERAs work by blocking endothelin-1, a potent vasoconstrictor, thereby reducing blood vessel constriction and lowering pulmonary blood pressure. PDE5Is enhance the effects of nitric oxide, leading to vasodilation and improved blood flow in the lungs. Prostacyclin Analogues mimic the effects of prostacyclin, a natural vasodilator, and inhibit platelet aggregation. These mechanisms are crucial for PAH patients as they help to alleviate symptoms, improve exercise capacity, and slow disease progression by targeting the underlying pathophysiological processes of the disease.