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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

Brief Summary: 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.

Detailed Summary:
Sponsor: Actelion

Current Primary Outcome: 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) ]

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



Original Primary Outcome: To demonstrate that either dose of ACT-064992 prolongs the time to first morbidity or mortality event in patients with symptomatic pulmonary arterial hypertension. [ Time Frame: End of Study ]

Current Secondary Outcome:

  • 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) ]
    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) ]
    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) ]
    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 ]
    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 ]

    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 ]
    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 ]
    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.


Original Secondary Outcome: To evaluate the safety and tolerability of ACT-064992 in patients with symptomatic pulmonary arterial hypertension [ Time Frame: End of Study ]

Information By: Actelion

Dates:
Date Received: April 14, 2008
Date Started: May 2008
Date Completion:
Last Updated: September 10, 2015
Last Verified: August 2015