Clinical Study to Evaluate the Effects of Macitentan on E... | NCT01743001

Status Module

Label	Type	Description	Intervention Names
Macitentan	Experimental	Subjects receive macitentan 10 mg oral tablet once daily	Drug: Macitentan 10 mg
Placebo	Placebo Comparator	Subjects receive macitentan-matching placebo oral tablet once daily	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Macitentan 10 mg	Drug	Macitentan 10 mg oral tablet once daily	Macitentan

Outcomes Module

Primary Outcomes

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 Outcomes

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.

Eligibility Module

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

Facility	Status	City	State	ZIP	Country	Contacts
Ahmanson/UCLA Heart Disease Center		Los Angeles	California	90095	United States
Stanford Hospital and Clinic

PubMed Identifier	Type	Citation	Retractions
30586694	Derived	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.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Macitentan	Subjects receive macitentan 10 mg, oral tablet, to be taken once daily
FG001	Placebo	Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Median

Full Range

Years

Title

Denominators

Categories

Title	Measurements
	BG00033.0(12 to 82) BG00131.0(13 to 62) BG00232.0(12 to 82)

Age, Customized

Count of Participants

Participants

Title

Denominators

Categories

12 - 17 years

Title	Measurements
	BG00013 BG0012 BG002

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00082 BG00168 BG002

Region of Enrollment

Asia-Pacific includes: China, Malaysia, Philippines, Vietnam; Eastern Europe: Bulgaria, Poland, Romania, Russian Federation, Serbia; Latin America: Chile, Mexico; North America: United States; Western Europe - Israel: Austria, France, Germany, Greece, Israel, Portugal, Spain, Turkey, United Kingdom

Count of Participants

Participants

Title

Denominators

Categories

Asia-Pacific

Title	Measurements
	BG00047 BG001

Body Mass Index (BMI)

Median

Full Range

kg/m^2

Title

Denominators

Categories

Title	Measurements
	BG00021.15(11.9 to 38.9) BG00121.55(14.5 to 42.2) BG002

WHO functional class

Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with 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. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure.

Per protocol patients in WHO functional class I were excluded.

Count of Participants

Participants

Title

Denominators

Categories

class I

Title	Measurements
	BG0000 BG001

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

Full analysis set: The analysis was performed on the full analysis set (FAS), i.e., all randomized subjects in the treatment group to which they were randomized and by imputing missing values at Week 16 according to pre-defined rules.

Posted

Mean

Standard Deviation

meter

From baseline to Week 16

ID	Title	Description
OG000	Macitentan	Subjects receive macitentan 10 mg, oral tablet, to be taken once daily
OG001	Placebo	Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily

Units	Counts
Participants	OG000114 OG001112

Title

Denominators

Categories

6MWD at baseline

Title	Measurements
	OG000368.7± 74.5 OG001380.3± 76.3

6MWD at Week 16

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	The null hypothesis was that there was no difference between macitentan and placebo for the mean change from baseline to Week 16 in 6MWD. Null hypothesis was tested by an analysis of covariance (ANCOVA).	ANCOVA	ANCOVA model included treatment group, presence of DS (yes/no), and WHO FC (II vs III/IV) as categorical factors, and baseline 6MWD value as covariate	0.6120	To control for multiplicity across the primary and secondary endpoints, all secondary endpoints were analyzed hierarchically according to order and significance as pre-specified in the protocol eliminating further adjustment for multiple comparisons.	least-square (LS) mean difference	-4.7			2-Sided	95	-22.8	13.5

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.

Posted

Count of Participants

Participants

From baseline to Week 16

ID	Title	Description
OG000	Macitentan	Subjects receive macitentan 10 mg, oral tablet, to be taken once daily
OG001	Placebo	Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily

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.

Posted

Mean

Standard Deviation

Score on a scale

From baseline to Week 16

ID	Title	Description
OG000	Macitentan	Subjects receive macitentan 10 mg, oral tablet, to be taken once daily
OG001	Placebo	Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily

Units	Counts
Participants

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.

Full analysis set (excluding children <14 years of age and Down Syndrome subjects)

Posted

Mean

Standard Deviation

Score on a scale

From baseline to Week 16

ID	Title	Description
OG000	Macitentan	Subjects receive macitentan 10 mg, oral tablet, to be taken once daily
OG001	Placebo	Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute kidney injury	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 events1 affected114 at risk EG0010 events0 affected112 at risk
Atrial fibrillation	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 events1 affected114 at risk EG0012 events1 affected112 at risk
Cardiac failure chronic	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 events0 affected114 at risk EG0011 events1 affected112 at risk
Dizziness	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 events1 affected114 at risk EG0010 events0 affected112 at risk
Endocarditis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 events1 affected114 at risk EG0010 events0 affected112 at risk
Pneumonia	Infections and infestations	MedDRA	Systematic Assessment	EG0002 events2 affected114 at risk EG0010 events0 affected112 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 events1 affected114 at risk EG0010 events0 affected112 at risk
Right ventricular failure	Cardiac disorders	MedDRA	Systematic Assessment	EG0004 events3 affected114 at risk EG0010 events0 affected112 at risk
Septic shock	Infections and infestations	MedDRA	Systematic Assessment	EG0001 events1 affected114 at risk EG0010 events0 affected112 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 events1 affected114 at risk EG0010 events0 affected112 at risk

ID	Term
D000081029	Pulmonary Arterial Hypertension
D004541	Eisenmenger Complex

ID	Term
D006976	Hypertension, Pulmonary
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D006330	Heart Defects, Congenital
D018376	Cardiovascular Abnormalities
D002318	Cardiovascular Diseases
D006331	Heart Diseases
D000013	Congenital Abnormalities
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities

ID	Title	Description
BG000	Macitentan	Subjects receive macitentan 10 mg, oral tablet, to be taken once daily
BG001	Placebo	Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Macitentan	Subjects receive macitentan 10 mg orally to be taken once daily. 114 subjects were exposed to Macitentan 10 mg for 15.93 weeks on average.	1	114	7	114	31	114
EG001	Placebo	Subjects receive macitentan-matching placebo orally to be taken once daily. 112 subjects were exposed to placebo for 15.96 weeks on average.	0	112	2	112	30	112

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Bronchitis	Infections and infestations	MedDRA	Systematic Assessment	EG0006 events6 affected114 at risk EG0013 events3 affected112 at risk
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 events0 affected114 at risk EG0018 events6 affected112 at risk
Headache	Nervous system disorders	MedDRA	Systematic Assessment	EG00015 events13 affected114 at risk EG0015 events5 affected112 at risk
Nasopharyngitis	Infections and infestations	MedDRA	Systematic Assessment	EG0004 events3 affected114 at risk EG00116 events14 affected112 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG00012 events11 affected114 at risk EG00110 events7 affected112 at risk