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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01743001
Recruitment Status : Completed
First Posted : December 6, 2012
Results First Posted : January 30, 2018
Last Update Posted : February 23, 2018
Information provided by (Responsible Party):

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

Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: Macitentan 10 mg Drug: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 226 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : May 21, 2013
Actual Primary Completion Date : December 1, 2016
Actual Study Completion Date : December 1, 2016

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 Name: ACT-064992
Placebo Comparator: Placebo
Subjects receive macitentan-matching placebo oral tablet once daily
Drug: Placebo
Macitentan-matching placebo oral tablet once daily

Primary Outcome Measures :
  1. Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD) [ Time Frame: From baseline to Week 16 ]
    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.

Secondary Outcome Measures :
  1. Change From Baseline to Week 16 in WHO Functional Class [ Time Frame: From baseline to Week 16 ]
    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.

  2. Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index [ Time Frame: From baseline to Week 16 ]
    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.

  3. Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire [ Time Frame: From baseline to Week 16 ]

    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.

Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01743001

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

Responsible Party: Actelion Identifier: NCT01743001     History of Changes
Other Study ID Numbers: AC-055-305
First Posted: December 6, 2012    Key Record Dates
Results First Posted: January 30, 2018
Last Update Posted: February 23, 2018
Last Verified: January 2018

Keywords provided by Actelion:
exercise capacity
Eisenmenger Syndrome

Additional relevant MeSH terms:
Familial Primary Pulmonary Hypertension
Eisenmenger Complex
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Heart Diseases
Congenital Abnormalities
Endothelin A Receptor Antagonists
Endothelin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Endothelin B Receptor Antagonists