Study of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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The AC-055-302/SERAPHIN study will be an event-driven Phase III study, comparing two different doses of macitentan (ACT-064992) (3 and 10 mg) vs placebo in patients with symptomatic PAH. The main study objective is to demonstrate that macitentan (ACT-064992) prolongs time to the first morbidity or mortality event, and to evaluate the benefit/risk profile of macitentan (ACT-064992) in the treatment of patients with symptomatic PAH.

Official Title
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A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group, Event-driven, Phase III Study to Assess the Effects of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: macitentan (ACT-064992)
* Drug: macitentan (ACT-064992)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent prior to initiation of any study mandated procedure. Patients with symptomatic pulmonary arterial hypertension (PAH) in modified World Health Organization (WHO) functional class II to IV. Patients with the following types of pulmonary arterial hypertension (PAH) belonging to groups 1.1 to 1.3 of the Venice classification: Idiopathic (IPAH); Familial (FPAH); or Related to: Collagen vascular disease; Simple, congenital systemic-to-pulmonary shunts at least 1 year post surgical repair; Human immunodeficiency virus (HIV) infection; or Drugs and toxins. PAH diagnosis confirmed by hemodynamic evaluation performed prior to randomization and showing all of the following: Mean pulmonary artery pressure (mPAP) > 25 mmHg at rest; Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) < 15 mmHg; and Pulmonary vascular resistance (PVR) at rest >= 320 dyn×sec/cm^5. 6-minute walk distance (6MWD) >= 50 m. Men or women > 12 years of age (women of childbearing potential must have a negative pre-treatment serum pregnancy test and must use a reliable method of contraception). Exclusion Criteria: PAH associated with portal hypertension, thyroid disorders, glycogen storage disease, Gaucher''s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy. PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and combined and complex systemic-to-pulmonary shunts, corrected or non corrected. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis. Persistent pulmonary hypertension of the newborn. Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification. Moderate to severe obstructive lung disease: forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 65% of predicted value after bronchodilator administration. Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of predicted value. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C. Estimated creatinine clearance < 30 mL/min Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal. Hemoglobin < 75% of the lower limit of the normal range. Systolic blood pressure < 100 mmHg. Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements. Pregnant or breast-feeding. Known concomitant life-threatening disease with a life expectancy < 12 months. Body weight < 40 kg. Any condition that prevents compliance with the protocol or adherence to therapy. Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to randomization. Systemic treatment within 4 week prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors). Treatment with cytochrome P3A (CYP3A) inducers within 4 weeks prior to randomization Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients. Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Macitentan (ACT-064992) tablet, 3 mg, once daily | Drug: macitentan (ACT-064992)<br>* Tablet, 3 mg dosage, once daily<br>|
| Experimental: 2<br>Macitentan (ACT-064992) tablet, 10 mg, once daily | Drug: macitentan (ACT-064992)<br>* Tablet, 10 mg dosage, once daily<br>|
| Placebo Comparator: 3<br>Matching placebo, once daily | Drug: placebo<br>* Matching placebo, once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Confirmed Morbidity or Mortality Event up to the End of Treatment (Kaplan-Meier Estimate of Patients Without a Morbidity or Mortality Event) | Morbidity or mortality events were defined as: a) Death; b) Atrial septostomy; c) Lung transplantation; d) Initiation of intravenous (i.v.) or subcutaneous prostanoids, or; e) Other worsening of pulmonary arterial hypertension (PAH). Other worsening of PAH was defined by the combined occurrence of all the following 3 events: At least 15% decrease in the 6 minute walk distance from baseline, confirmed by 2 tests performed on separate days, within 2 weeks. AND worsening of PAH symptoms including at least one of the following: a) Increase in WHO Functional Class (WHO FC), or no change in patients in WHO FC IV at baseline; b) Appearance or worsening of signs of right heart failure that did not respond to optimized oral diuretic therapy AND need for new treatment(s) for PAH that included the following: a) Oral or inhaled prostanoids; b) Oral phosphodiesterase inhibitors; c) Endothelin receptor antagonists (only after discontinuation of study treatment; d) i.v. diuretics | Up to end of treatment (data presented up to month 36) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Events of PAH or hospitalization for PAH up to the end of treatment included: death due to PAH, or onset of a treatment-emergent adverse event with a fatal outcome due to PAH occurring up to 4 weeks after the end of treatment, or hospitalisation for PAH up to the end of treatment. | Up to end of treatment (data presented up to month 36) | 
| Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Events of death due to any cause up to the end of treatment (plus 7 days) | Up to end of treatment (data presented up to month 36) | 
| Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Events of death due to any cause up to the end of study (EOS). The initiation of EOS procedure occurred when the target of 285 events was expected to have been achieved (30 January 2012). | Up to end of study (data presented up to month 36) | 
| Change From Baseline to Month 6 in 6-minute Walk Distance | The 6-minute walk test (6MWT) is a non-encouraged test, performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. These guidelines were provided to all sites. For patients who had never performed a 6MWT previously, a training test was required before the qualifying tests for inclusion were performed. | Baseline to month 6 | 
| Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6 | Class I: no limitation of usual physical activity (PA) which does not increase dyspnea, fatigue, chest pain, or presyncope. Class II: mild limitation of PA. No discomfort at rest. Normal PA increases dyspnea, fatigue, chest pain, or presyncope. Class III: marked limitation of PA. No discomfort at rest. Less than ordinary activity increases dyspnea, fatigue, chest pain, or presyncope. Class IV: unable to perform any PA and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any PA. | Baseline to month 6 | 
| Pulmonary Vascular Resistance at Baseline and Month 6 | In a sub-study, hemodynamic variables were assessed at baseline and Month 6. If the patient had undergone a right heart catheterization during the 3 months prior to randomization, these results were to be used as baseline values, if the background therapy had not changed during the intervening period. | Baseline to month 6 | 
| Cardiac Index at Baseline and Month 6 | In a sub-study, hemodynamic variables were assessed at baseline and Month 6. If the patient had undergone a right heart catheterization during the 3 months prior to randomization, these results were to be used as baseline values, if the background therapy had not changed during the intervening period. | Baseline to month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary arterial hypertension SERAPHIN