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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01743001
Other study ID # AC-055-305
Secondary ID
Status Completed
Phase Phase 3
First received November 29, 2012
Last updated February 22, 2018
Start date May 21, 2013
Est. completion date December 1, 2016

Study information

Verified date January 2018
Source Actelion
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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


Recruitment information / eligibility

Status Completed
Enrollment 226
Est. completion date December 1, 2016
Est. primary completion date December 1, 2016
Accepts healthy volunteers No
Gender All
Age group 12 Years and older
Eligibility 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 Design


Related Conditions & MeSH terms


Intervention

Drug:
Macitentan 10 mg
Macitentan 10 mg oral tablet once daily
Placebo
Macitentan-matching placebo oral tablet once daily

Locations

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

Sponsors (1)

Lead Sponsor Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Vietnam,  Austria,  Bulgaria,  Chile,  China,  France,  Germany,  Greece,  Israel,  Malaysia,  Mexico,  Philippines,  Poland,  Portugal,  Romania,  Russian Federation,  Serbia,  Spain,  Turkey,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 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
Secondary 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
Secondary 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
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