Clinical Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome (MAESTRO)

A Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase 3 Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome

Clinical study to assess the efficacy, safety, and tolerability of macitentan in subjects with Eisenmenger Syndrome.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Macitentan 10 mg; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 226
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, A-1090
    • Gen Hosp Univ Vienna Dept Cardiology
• Bulgaria
  • Sofia, Bulgaria, 1309
    • Mhat Nat Card Hosp - Cardiology Clinic
  • Sofia, Bulgaria, 1309
    • Mhat Nat Card Hosp - Pediatric Clin / Ped Card Dept
  • Sofia, Bulgaria, 1750
    • Mhat Sveta Anna Clin Card
• Chile
  • Providencia, Chile
    • Inst Nat Torax, Unidad Cardiopatia Congenitas Del Adulto
  • Santiago, Chile, 7650018
    • Clinica Tabancura - Cardio Unit
• China
  • Beijing, China, 100029
    • Beijing Anzhen Hospital, Cardiology Dpt
  • Beijing, China, 100037
    • Cardiovascular Institute&Fuwai Hospital
  • Shanghai, China, 200433
    • Shanghai Pulmonary Hospital, Dept of Pulmonary Circulation
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Guangdong General Hospital, Cardiology Dpt
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Wu Han Asia Heart Hosp
  • Liaoning
    • Shenyang, Liaoning, China, 110016
      • The General Hosp of Shenyang Military Region
• France
  • Marseille Cedex 5, France, 13385
    • Hosp La Timone - Dept Pediatric Cardiology
  • Nantes Cedex 1, France, 44093
    • Hosp Laennec - Dept Cardiology
  • Paris Cedex 15, France, 75908
    • Hosp Pompidou - Dept Congenital Cardiac Diseases
  • Pessac, France, 33604
    • Hosp Cardiology Haut Leveque - Dept Congenital Diseases
• Germany
  • Berlin, Germany, 13353
    • Herzzentrum Berlin, Ped Cardiology
  • Giessen, Germany, 35392
    • Universitätsklinikum Giessen - Pediatric Heart Center
  • Heidelberg, Germany, D-69120
    • Uni Heidelberg - Kinderkardiologie
• Greece
  • Thessaloniki, Greece, 54636
    • Ahepa University General hospital
• Israel
  • Petach Tikvah, Israel, 49100
    • Rabin Medical Centre - Pulmonology
• Malaysia
  • Kuala Lumpur, Malaysia, 50400
    • Institut Jantung Negara
• Mexico
  • Mexico City, Mexico, 14080
    • Instituto Nacional de Cardiologia (INC) Ignacio Chavez
  • Querétaro, Mexico
    • Instituto de Corazón de Querétaro
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64718
      • Unidad de Investigacion Clin En Med, Sc (Udicem)
• Philippines
  • Manila, Philippines
    • PHC, MAB
• Poland
  • Gdańsk, Poland, 80-952
    • Cardiology Gdańsk Univ
  • Krakow, Poland, 31-202
    • Cardiology Kraków Univ
  • Wrocław, Poland, 51-124
    • Cardiology Wrocław
• Portugal
  • Coimbra, Portugal, 3000-075
    • Hosp Univ Coimbra - Dpt Cardiology
  • Lisboa, Portugal, 1169-024
    • Hosp Sta Marta - Dept Cardiology
• Romania
  • Bucuresti, Romania, 022328
    • Er Inst For Cardvasc Dis "Prof Dr Cc Iliescu" - Card Ii
  • Targu-Mures, Romania, 540136
    • Cardio Med SRL
  • Timisoara, Romania, 300312
    • Clin Hosp For Inf and Pulm Dis Victor Babes - Ii Pulm
• Russian Federation
  • Kemerovo, Russian Federation, 650002
    • Sci Institute Systemic Problems Cardio Diseases Kemerovo
  • Moscow, Russian Federation, 121552
    • Russian Cardiology Scientific and Production Complex
  • St Petersburg, Russian Federation, 197341
    • V. A. Almazov Institute of Cardiology
• Serbia
  • Belgrade, Serbia, 11040
    • Dedinje Cardiovasc Inst - Cardiovasc Research Ctr
  • Belgrade, Serbia, 11070
    • Mother and Child Health Care Inst "Dr Vukan Cupic"
  • Belgrade, Serbia, 11080
    • Clin Hosp Ctr Zemun - Cardiology Dept
• Spain
  • Barcelona, Spain, 08035
    • Hosp Univ Vall D'Hebron - Dpt Congenital Heart Disease Adult
  • Sevilla, Spain, 41007
    • Hosp Univ Virgen Macarena - Dpt Cardiology
  • Valencia, Spain, 46009
    • Hosp Universitario La Fe Dpt Cardiology
• Turkey
  • Samsun, Turkey, 55139
    • Omu Pediatry
• United Kingdom
  • Bristol, United Kingdom, BS2 8BJ
    • Bristol Univ Hosp Congenital Heart Centre
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Ahmanson/UCLA Heart Disease Center
    • Palo Alto, California, United States, 94304
      • Stanford Hospital and Clinic
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital/The Emory Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Barnes-Jewish Hosp/Wash Univ School of Med
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Children's Heart Center Nevada
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Nationwide Children's Hospital
  • Texas
    • Houston, Texas, United States, 77030-2303
      • Texas Children'S Hosp - Dept of Cardiology
• Vietnam
  • Hanoi, Vietnam
    • Hanoi Medical University Hospital
  • Ho Chi Minh, Vietnam
    • Children'S Hospital, Ho Chi Minh
  • Ho Chi Minh, Vietnam
    • Tam Duc Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects:

  • not participating in the hemodynamic sub-study: males or females ≥ 12 years of age.
  • participating in the hemodynamic sub-study: males or females ≥ 18 years of age.

• Subjects (including those with Down Syndrome [DS]) with confirmed Eisenmenger Syndrome [ES] (European Society of Cardiology [ESC] and the European Respiratory Society [ERS] guidelines):

  1. Established by echocardiography as:

     • Large congenital shunting defect at atrial, ventricular or arterial level*
     • and right to left shunt or bi-directional shunt with prevalent right to left direction.
  2. Resting peripheral oxygen saturation (SpO2) ≤ 90% and > 70% (pulse oximetry, room air).

The lower limit is 65% if a subject is living at an altitude greater than 2500 m above sea level.

*Subjects with any of the following open defects are eligible for the study either as an isolated defect or in combination:

• atrial septal defect (ASD)
• ventricular septal defect (VSD)
• partial or complete atrioventricular septal defect (AVSD)
• patent ductus arteriosus (PDA)
• aortopulmonary window (AP window)
• total or partial anomalous pulmonary venous return (TAPVR, PAPVR) The defects may be either unoperated or previously palliated surgically (provided significant residual defect remains).

The Steering Committee will review the echocardiography data of all subjects (main study and sub study) to confirm eligibility prior to Randomization.

• Subjects with the following findings at cardiac catheterization:

  • Mean resting pulmonary arterial pressure (mPAP) > 25 mmHg
  • Pulmonary capillary wedge pressure (PCWP) or mean left atrial pressure (LAP) or left ventricular end diastolic pressure (LVED) ≤ 15 mmHg
  • Pulmonary vascular resistance (PVR) ≥ 800 dyn∙s/cm5 or ≥ 10 Wood units
• Subjects with WHO functional class ≥ II.
• Subjects able to reliably perform the the 6-minute walk test (6MWT) with a minimum distance of 50 m and a maximum distance of 450 m.

Exclusion Criteria:

- Main study and hemodynamic sub-study: Any of the following conditions previously known or identified via cardiac catheterization or echocardiography:

• Pulmonary arterial or venous stenosis > 25% size of native pulmonary artery (PA) or pulmonary vein
• Severe tricuspid regurgitation in the setting of left to right shunt at the ventricular or atrial level
• Greater than mild tricuspid stenosis
• Intracavitary RV outflow obstruction
• Greater than mild mitral stenosis
• Intracavitary LV outflow obstruction
• Subvalvular or supravalvular aortic stenosis
• Aortic coarctation
• Greater than moderate mitral regurgitation
• Recognized extracardiac systemic venous collaterals to the pulmonary venous circulation
• Recognized hepatic wedge pressure-inferior vena cava pressure gradient >12 mm Hg
• PCWP "v" waves >20 mmHg
• Tetralogy of Fallot
• Truncus arteriosus
• Interrupted aortic arch
• Transposition of great arteries
• Single ventricle defects: absent AV connection (mitral or tricuspid atresia), double inlet AV connections left or right ventricle, functional univentricular heart (unbalanced AVSD, hypoplastic RV, double outlet RV), hypoplastic left heart syndrome
• Ebstein's anomaly
• Severe aortic regurgitation
• Pulmonary atresia
• PAPVR or TAPVR, ONLY if there is lung hypoplasia or if documentation confirming the absence of lung hypoplasia does not exist.

For subjects participating in the hemodynamic sub-study the following will also be considered exclusion criteria:

• SVC stenosis >25% size of native vessel
• PDA, AP window, TAPVR, PAPVR, or ASD sinus venosus with anomalous pulmonary veins

• Down Syndrome

  • Subjects with deterioration of their clinical status within 3 months prior to Screening or during the Screening period.
  • Known moderate-to-severe restrictive (i.e., total lung capacity [TLC] < 60% of predicted value) or obstructive lung disease (i.e., forced expiratory volume in one second [FEV1] < 80 % of predicted value, and with FEV1 / forced vital capacity [FVC] < 70%)
  • Treatment with prostanoids within 1 month prior to Randomization
  • Subjects who initiated a PDE-5 inhibitor within 1 month prior to Randomization or those on a PDE-5 inhibitor for whom the dose has not been stable within 1 month prior to Randomization
  • Treatment with endothelin receptor antagonists (ERAs) within 1 month prior to Randomization
  • Subjects who initiated diuretics within 1 week prior to Randomization or subjects whose diuretic treatment has not been stable for at least 1 week prior to Randomization
  • Subjects being considered for an organ transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Macitentan; Subjects receive macitentan 10 mg oral tablet once daily	Drug: Macitentan 10 mg; Macitentan 10 mg oral tablet once daily; Other Names: ACT-064992
Placebo Comparator: Placebo; Subjects receive macitentan-matching placebo oral tablet once daily	Drug: Placebo; Macitentan-matching placebo oral tablet once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD)	The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.	From baseline to Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 16 in WHO Functional Class	A shift in WHO functional classes is considered an 'improvement' when shifting to a lower class (e.g. from class III to class II) or a 'worsening' when shifting to a higher class (e.g. from class III to class IV). Definition of functional classes as follows - Class I: no symptoms with exercise or at rest. Class II: No symptoms at rest but uncomfortable and short of breath with normal activity such as climbing a flight of stairs, grocery shopping, or making the bed. Class III: May not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting (e.g. doing normal chores around the house, have to take breaks while doing activities of daily living). Class IV: Symptoms at rest and severe symptoms with any activity. Most patients also have edema in the feet and ankles as result of right heart failure.	From baseline to Week 16
Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index	This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 16 compared to baseline. The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement.	From baseline to Week 16
Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire	The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of the functional health and well-being scores (i.e., physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health), as well as psychometrically based physical and mental health summary measures and a preference-based health utility (health rated as much better now than one year ago to much worse now than one year ago). It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group. For each of the domains and scores that the SF36 measures an aggregate percentage score is produced. The percentage scores range from 0% (lowest or worst possible level of functioning) to 100% (highest or best possible level of functioning). A higher score for the individual domains and summary component scores indicates a better condition of the subject.	From baseline to Week 16

Collaborators and Investigators

• Sponsor: Actelion

Publications and helpful links

General Publications

• Gatzoulis MA, Landzberg M, Beghetti M, Berger RM, Efficace M, Gesang S, He J, Papadakis K, Pulido T, Galie N; MAESTRO Study Investigators. Evaluation of Macitentan in Patients With Eisenmenger Syndrome. Circulation. 2019 Jan 2;139(1):51-63. doi: 10.1161/CIRCULATIONAHA.118.033575.

Study record dates

Study Major Dates

• Study Start (Actual): May 21, 2013
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: November 29, 2012
• First Submitted That Met QC Criteria: December 4, 2012
• First Posted (Estimate): December 6, 2012

Study Record Updates

• Last Update Posted (Actual): February 23, 2018
• Last Update Submitted That Met QC Criteria: February 22, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: exercise capacity; Eisenmenger Syndrome
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Congenital Abnormalities; Hypertension, Pulmonary; Heart Defects, Congenital; Cardiovascular Abnormalities; Hypertension; Pulmonary Arterial Hypertension; Eisenmenger Complex; Molecular Mechanisms of Pharmacological Action; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Macitentan
• Other Study ID Numbers: AC-055-305