Clinical trial NCT01743001: Clinical Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Keywords: exercise capacity
Eisenmenger Syndrome
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2012-12-06
Enrollment: 226
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Clinical study to assess the efficacy, safety, and tolerability of macitentan in subjects with 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):

  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

Primary outcomes:
measure: Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD)
timeFrame: From baseline to Week 16
Secondary outcomes:
measure: Change From Baseline to Week 16 in WHO Functional Class
timeFrame: From baseline to Week 16
measure: Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index
timeFrame: From baseline to Week 16
measure: Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire
timeFrame: From baseline to Week 16
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Ahmanson/UCLA Heart Disease Center
state: California
city: Palo Alto
country: United States
facility: Stanford Hospital and Clinic
state: California
city: Atlanta
country: United States
facility: Emory University Hospital/the Emory Clinic
state: Georgia
city: Saint Louis
country: United States
facility: Barnes-Jewish Hosp/Wash Univ School of Med
state: Missouri
city: Las Vegas
country: United States
facility: Children'S Heart Center Nevada
state: Nevada
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Houston
country: United States
facility: Texas Children'S Hosp - Dept of Cardiology
state: Texas
city: Vienna
country: Austria
facility: Gen Hosp Univ Vienna Dept Cardiology
city: Sofia
country: Bulgaria
facility: Mhat Nat Card Hosp - Cardiology Clinic
city: Sofia
country: Bulgaria
facility: Mhat Nat Card Hosp - Pediatric Clin / Ped Card Dept
city: Sofia
country: Bulgaria
facility: Mhat Sveta Anna Clin Card
city: Providencia
country: Chile
facility: Inst Nat Torax, Unidad Cardiopatia Congenitas Del Adulto
city: Santiago
country: Chile
facility: Clinica Tabancura - Cardio Unit
city: Guangzhou
country: China
facility: Guangdong General Hospital, Cardiology Dpt
state: Guangdong
city: Wuhan
country: China
facility: Wu Han Asia Heart Hosp
state: Hubei
city: Shenyang
country: China
facility: The General Hosp of Shenyang Military Region
state: Liaoning
city: Beijing
country: China
facility: Beijing Anzhen Hospital, Cardiology Dpt
city: Beijing
country: China
facility: Cardiovascular Institute&Fuwai Hospital
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital, Dept of Pulmonary Circulation
city: Marseille Cedex 5
country: France
facility: Hosp La Timone - Dept Pediatric Cardiology
city: Nantes Cedex 1
country: France
facility: Hosp Laennec - Dept Cardiology
city: Paris Cedex 15
country: France
facility: Hosp Pompidou - Dept Congenital Cardiac Diseases
city: Pessac
country: France
facility: Hosp Cardiology Haut Leveque - Dept Congenital Diseases
city: Berlin
country: Germany
facility: Herzzentrum Berlin, Ped Cardiology
city: Giessen
country: Germany
facility: Universitätsklinikum Giessen - Pediatric Heart Center
city: Heidelberg
country: Germany
facility: Uni Heidelberg - Kinderkardiologie
city: Thessaloniki
country: Greece
facility: Ahepa University General Hospital
city: Petach Tikvah
country: Israel
facility: Rabin Medical Centre - Pulmonology
city: Kuala Lumpur
country: Malaysia
facility: Institut Jantung Negara
city: Monterrey
country: Mexico
facility: Unidad de Investigacion Clin En Med, Sc (Udicem)
state: Nuevo Leon
city: Mexico City
country: Mexico
facility: Instituto Nacional de Cardiologia (Inc) Ignacio Chavez
city: Querétaro
country: Mexico
facility: Instituto de Corazon de Querètaro
city: Manila
country: Philippines
facility: PHC, MAB
city: Gdańsk
country: Poland
facility: Cardiology Gdańsk Univ
city: Krakow
country: Poland
facility: Cardiology Kraków Univ
city: Wrocław
country: Poland
facility: Cardiology Wrocław
city: Coimbra
country: Portugal
facility: Hosp Univ Coimbra - Dpt Cardiology
city: Lisboa
country: Portugal
facility: Hosp Sta Marta - Dept Cardiology
city: Bucuresti
country: Romania
facility: Er Inst For Cardvasc Dis "Prof Dr Cc Iliescu" - Card Ii
city: Targu-Mures
country: Romania
facility: Cardio Med Srl
city: Timisoara
country: Romania
facility: Clin Hosp For Inf and Pulm Dis Victor Babes - Ii Pulm
city: Kemerovo
country: Russian Federation
facility: Sci Institute Systemic Problems Cardio Diseases Kemerovo
city: Moscow
country: Russian Federation
facility: Russian Cardiology Scientific and Production Complex
city: St Petersburg
country: Russian Federation
facility: V. A. Almazov Institute of Cardiology
city: Belgrade
country: Serbia
facility: Dedinje Cardiovasc Inst - Cardiovasc Research Ctr
city: Belgrade
country: Serbia
facility: Mother and Child Health Care Inst "Dr Vukan Cupic"
city: Belgrade
country: Serbia
facility: Clin Hosp Ctr Zemun - Cardiology Dept
city: Barcelona
country: Spain
facility: Hosp Univ Vall D'Hebron - Dpt Congenital Heart Disease Adult
city: Sevilla
country: Spain
facility: Hosp Univ Virgen Macarena - Dpt Cardiology
city: Valencia
country: Spain
facility: Hosp Universitario La Fe Dpt Cardiology
city: Samsun
country: Turkey
facility: Omu Pediatry
city: Bristol
country: United Kingdom
facility: Bristol Univ Hosp Congenital Heart Centre
city: Hanoi
country: Vietnam
facility: Hanoi Medical University Hospital
city: Ho Chi Minh
country: Vietnam
facility: Children's Hospital, Ho Chi Minh
city: Ho Chi Minh
country: Vietnam
facility: Tam Duc Hospital
Study officials:
References:
citation: 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.