Clinical Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome (MAESTRO)
Pulmonary Arterial Hypertension
About this trial
This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring exercise capacity, Eisenmenger Syndrome
Eligibility Criteria
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):
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.
- 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
Sites / Locations
- Ahmanson/UCLA Heart Disease Center
- Stanford Hospital and Clinic
- Emory University Hospital/the Emory Clinic
- Barnes-Jewish Hosp/Wash Univ School of Med
- Children'S Heart Center Nevada
- Nationwide Children's Hospital
- Texas Children'S Hosp - Dept of Cardiology
- Gen Hosp Univ Vienna Dept Cardiology
- Mhat Nat Card Hosp - Cardiology Clinic
- Mhat Nat Card Hosp - Pediatric Clin / Ped Card Dept
- Mhat Sveta Anna Clin Card
- Inst Nat Torax, Unidad Cardiopatia Congenitas Del Adulto
- Clinica Tabancura - Cardio Unit
- Guangdong General Hospital, Cardiology Dpt
- Wu Han Asia Heart Hosp
- The General Hosp of Shenyang Military Region
- Beijing Anzhen Hospital, Cardiology Dpt
- Cardiovascular Institute&Fuwai Hospital
- Shanghai Pulmonary Hospital, Dept of Pulmonary Circulation
- Hosp La Timone - Dept Pediatric Cardiology
- Hosp Laennec - Dept Cardiology
- Hosp Pompidou - Dept Congenital Cardiac Diseases
- Hosp Cardiology Haut Leveque - Dept Congenital Diseases
- Herzzentrum Berlin, Ped Cardiology
- Universitätsklinikum Giessen - Pediatric Heart Center
- Uni Heidelberg - Kinderkardiologie
- Ahepa University General Hospital
- Rabin Medical Centre - Pulmonology
- Institut Jantung Negara
- Unidad de Investigacion Clin En Med, Sc (Udicem)
- Instituto Nacional de Cardiologia (Inc) Ignacio Chavez
- Instituto de Corazon de Querètaro
- PHC, MAB
- Cardiology Gdańsk Univ
- Cardiology Kraków Univ
- Cardiology Wrocław
- Hosp Univ Coimbra - Dpt Cardiology
- Hosp Sta Marta - Dept Cardiology
- Er Inst For Cardvasc Dis "Prof Dr Cc Iliescu" - Card Ii
- Cardio Med Srl
- Clin Hosp For Inf and Pulm Dis Victor Babes - Ii Pulm
- Sci Institute Systemic Problems Cardio Diseases Kemerovo
- Russian Cardiology Scientific and Production Complex
- V. A. Almazov Institute of Cardiology
- Dedinje Cardiovasc Inst - Cardiovasc Research Ctr
- Mother and Child Health Care Inst "Dr Vukan Cupic"
- Clin Hosp Ctr Zemun - Cardiology Dept
- Hosp Univ Vall D'Hebron - Dpt Congenital Heart Disease Adult
- Hosp Univ Virgen Macarena - Dpt Cardiology
- Hosp Universitario La Fe Dpt Cardiology
- Omu Pediatry
- Bristol Univ Hosp Congenital Heart Centre
- Hanoi Medical University Hospital
- Children's Hospital, Ho Chi Minh
- Tam Duc Hospital
Arms of the Study
Arm 1
Arm 2
Experimental
Placebo Comparator
Macitentan
Placebo
Subjects receive macitentan 10 mg oral tablet once daily
Subjects receive macitentan-matching placebo oral tablet once daily