Trial record 2 of 2 for:    actelion seraphin

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Actelion
ClinicalTrials.gov Identifier:
NCT00660179
First received: April 14, 2008
Last updated: April 3, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Pulmonary Arterial Hypertension
Drug: macitentan (ACT-064992)
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Actelion:

Primary Outcome Measures:
  • 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) [ Time Frame: Up to end of treatment (data presented up to month 36) ] [ Designated as safety issue: No ]

    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



Secondary Outcome Measures:
  • Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) [ Time Frame: Up to end of treatment (data presented up to month 36) ] [ Designated as safety issue: No ]
    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.

  • Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) [ Time Frame: Up to end of treatment (data presented up to month 36) ] [ Designated as safety issue: No ]
    Events of death due to any cause up to the end of treatment (plus 7 days)

  • Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) [ Time Frame: Up to end of study (data presented up to month 36) ] [ Designated as safety issue: No ]
    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).

  • Change From Baseline to Month 6 in 6-minute Walk Distance [ Time Frame: Baseline to month 6 ] [ Designated as safety issue: No ]
    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.

  • Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6 [ Time Frame: Baseline to month 6 ] [ Designated as safety issue: No ]

    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.


  • Pulmonary Vascular Resistance at Baseline and Month 6 [ Time Frame: Baseline to month 6 ] [ Designated as safety issue: No ]
    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.

  • Cardiac Index at Baseline and Month 6 [ Time Frame: Baseline to month 6 ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Summary of the First Causes of Morbidity or Mortality [ Time Frame: Up to end of treatment (Up to 36 months) ] [ Designated as safety issue: No ]

    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



Enrollment: 742
Study Start Date: May 2008
Study Completion Date: April 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Macitentan (ACT-064992) tablet, 3 mg, once daily
Drug: macitentan (ACT-064992)
Tablet, 3 mg dosage, once daily
Experimental: 2
Macitentan (ACT-064992) tablet, 10 mg, once daily
Drug: macitentan (ACT-064992)
Tablet, 10 mg dosage, once daily
Placebo Comparator: 3
Matching placebo, once daily
Drug: placebo
Matching placebo, once daily

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent prior to initiation of any study mandated procedure.
  2. Patients with symptomatic pulmonary arterial hypertension (PAH) in modified World Health Organization (WHO) functional class II to IV.
  3. 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.
  4. 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.
  5. 6-minute walk distance (6MWD) >= 50 m.
  6. 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:

  1. PAH associated with portal hypertension, thyroid disorders, glycogen storage disease, Gaucher''s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy.
  2. PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and combined and complex systemic-to-pulmonary shunts, corrected or non corrected.
  3. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis.
  4. Persistent pulmonary hypertension of the newborn.
  5. Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification.
  6. 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.
  7. Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of predicted value.
  8. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
  9. Estimated creatinine clearance < 30 mL/min
  10. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal.
  11. Hemoglobin < 75% of the lower limit of the normal range.
  12. Systolic blood pressure < 100 mmHg.
  13. Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements.
  14. Pregnant or breast-feeding.
  15. Known concomitant life-threatening disease with a life expectancy < 12 months.
  16. Body weight < 40 kg.
  17. Any condition that prevents compliance with the protocol or adherence to therapy.
  18. Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise.
  19. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to randomization.
  20. Systemic treatment within 4 week prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors).
  21. Treatment with cytochrome P3A (CYP3A) inducers within 4 weeks prior to randomization
  22. Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.
  23. Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00660179

  Show 153 Study Locations
Sponsors and Collaborators
Actelion
Investigators
Study Chair: Loic Perchenet, PhD Actelion
  More Information

Publications:
Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT00660179     History of Changes
Other Study ID Numbers: AC-055-302
Study First Received: April 14, 2008
Results First Received: November 5, 2013
Last Updated: April 3, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
Australia: Department of Health and Ageing Therapeutic Goods Administration
Austria: Federal Ministry for Health and Women
Belarus: Ministry of Health
Belgium: Federal Agency for Medicinal Products and Health Products
Canada: Health Canada
Chile: Instituto de Salud Pública de Chile
China: Food and Drug Administration
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Israel: Ministry of Health
Italy: The Italian Medicines Agency
Mexico: Ministry of Health
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Russia: Ministry of Health of the Russian Federation
Slovakia: State Institute for Drug Control
South Africa: Medicines Control Council
Taiwan: Department of Health
Ukraine: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Actelion:
pulmonary arterial hypertension SERAPHIN

Additional relevant MeSH terms:
Hypertension, Pulmonary
Hypertension
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on August 19, 2014