MERIT-1: Clinical Study to Assess the Efficacy, Safety and Tolerability of Macitentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02021292
• Collaborator: (none)
• Enrollment: 80
• Locations: 36
• Arms: 2
• Actual Duration (Months): 25.3
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Study to evaluate if macitentan is efficient, safe and tolerable enough to be used for treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH).

Condition or Disease	Intervention/Treatment	Phase
Chronic Thromboembolic Pulmonary Hypertension	Drug: Macitentan; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Prospective, Randomized, Placebo-controlled, Double-blind, Multicenter, Parallel-group, 24-week Study to Assess the Efficacy, Safety and Tolerability of Macitentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension
• Actual Study Start Date: Aug 20, 2014
• Actual Primary Completion Date: Sep 28, 2016
• Actual Study Completion Date: Sep 28, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Macitentan Macitentan 10 mg, oral tablet, to be taken once daily.	Drug: Macitentan; Macitentan 10 mg, oral tablet, to be taken once daily.; Other Names: ACT-064992
Placebo Comparator: Placebo Matching placebo oral tablet, to be taken once daily.	Drug: Placebo; Matching placebo oral tablet, to be taken once daily.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest. [From baseline to Week 16]

   The primary efficacy endpoint is defined as the PVR at rest at Week 16 expressed as percent of baseline PVR at rest.

Secondary Outcome Measures

1. Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD). [From baseline to Week 24]

   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.

2. Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT). [From baseline to Week 24]

   This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 24 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. Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 [From baseline to Week 24]

   WHO functional classes are defined as follows: 1) class I: no symptoms with exercise or at rest. No limitation of activity. 2) 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). 3) class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. 4) class IV: symptoms at rest (such as dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms (e.g. may faint especially while bending over with their heads lowered). Patients in class IV manifest signs of right heart failure. Shifting to a higher class (e.g. from class III to class IV) represents a 'worsening' while shifting to a lower class (e.g. from class III to class II) means an 'improvement'.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 84 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent

• Subject with CTEPH (WHO Group 4) judged as inoperable due to the localization of the obstruction being surgically inaccessible (i.e., distal disease).

• Female of childbearing potential must have a negative pre-treatment serum pregnancy test, be advised on appropriate methods of contraception, and agree to use 2 reliable methods of contraception.

Exclusion Criteria:

• Previous pulmonary endarterectomy.

• Recurrent thromboembolism despite sufficient oral anticoagulants.

• Symptomatic acute pulmonary embolism in the 6-month period prior to randomization.

• Known moderate-to-severe restrictive lung disease (i.e., TLC < 60% of predicted value) or obstructive lung disease (i.e., FEV1 < 70% of predicted, with FEV1/FVC < 65%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema).

• Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements in the 3-month period prior to Screening visit or during the Screening period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital Gasthuisberg / Interne Geneeskunde - I.G. Pneumologie	Leuven		Belgium	3000
2	Beijing Chao-Yang Hospital-Department of Respiration	Beijing		China	100020
3	Cardiovascular institute & Fuwai Hospital- Thrombus Center	Beijing		China	100037
4	The first affiliated hospital of guangzhou medical university-respiratory department	Guangzhou		China	510120
5	ngShanghai Pulmonary Hospital, Department of Pulmonary Circulation	Shanghai		China	200433
6	The General Hospital of Shenyang Military Region,Congenital Heart Disease Department	Shenyang		China	110016
7	Wuhan Asia Heart Hospital	Wuhan		China	430022
8	Centre for PPH, Charles University , II Interni klinika1.LF a VFN	Praha		Czechia	128 08
9	CHU de Bicêtre	Le Kremlin-Bicêtre cedex		France	94275
10	Hôpital Européen Georges Pompidou Service de Pneumologie, soins intensifs et endoscopies bronchiques	Paris cedex 15		France	75908
11	CHU de Toulouse Hopital Larrey	Toulouse Cedex 9		France	31059
12	Justus-Liebig-Universität Gießen	Giessen		Germany	35392
13	Thoraxklinik am Universitätsklinikum Heidelberg	Heidelberg		Germany	69126
14	Missionsärztliche Klinik gGmbH Akademisches Lehrkrankenhaus der Julius-Maximilians-Universität	Würzburg		Germany	97074
15	Semmelweis Egyetem	Budapest		Hungary	1125
16	Debreceni Egyetem Orvos- és Egészségtudományi Centrum, Kardiológiai Klinika	Debrecen		Hungary	4032
17	Severance Hospital, YonSei University Health System	Seoul		Korea, Republic of	3722
18	Lietuvos Sveikatos Mokslų Universiteto Ligoninės Kauno Klinikos Pulmonologijos-Imunologijos Klinika	Kaunas		Lithuania	50161
19	Instituto Nacional de Cardiologia (INC) Ignacio Chavez	Mexico City		Mexico	14080
20	Wojewódzki Szpital Specjalistyczny w Lublinie im. Stefana Kardynała Wyszyńskiego SPZOZ Oddział Kardiologii - Pododdział Intensywnego Nadzoru Kardiologicznego	Lublin		Poland	20-718
21	Wojewódzki Szpital Specjalistyczny we Wrocawiu	Wrocaw		Poland	51-124
22	Federal State Budgetary Institution "Scientific Research Institute of Systemic Problems of Cardiovascular Diseases", Siberian branch of RAMS	Kemerovo		Russian Federation	650002
23	Federal State Budgetary Institution "Russian Cardiology Scientific and Production Complex" of the Ministry of Health Care of the Russian Federation	Moscow		Russian Federation	121552
24	E.N.Meshalkin Novosibirsk State Research Institute Of Circulation Pathology Rosmedtechnology	Novosibirsk		Russian Federation	630055
25	Federal State Institution "Federal center of Heart, Blood and Endocrinology named after V.A.Almazov Rosmedtekhnologies"	St. Petersburg		Russian Federation	197341
26	Federal State Budgetary Institution "Research Institute for Cardiology" of Siberian Branch under the Russian Academy of Medical Sciences / Cardiovascular Surgery Department	Tomsk		Russian Federation	634012
27	University Hospital Zürich	Zürich		Switzerland	8091
28	King Chulalongkorn Memorial Hospital, Division of Respiratory and Respiratory Critical Care Medicine	Bangkok		Thailand	10330
29	Siriraj Hospital, Division of Respiratory Disease and Tuberculosis	Bangkok		Thailand	10700
30	MAHARAJ NAKORN CHIANG MAI HOSPITAL, Department of Internal Medicine	Chiang Mai		Thailand	50200
31	Istanbul University İstanbul Faculty Medicine Pulmonology Department	Capa_Istanbul		Turkey	34093
32	State Institute of Phthisiology and Pulmonology n.a. F.G. Yanovskiy of AMS Ukraine	Kyiv		Ukraine	03680
33	Lviv Regional Clinical Hospital, Cardiosurgery Department	Lviv		Ukraine	79014
34	Papworth Hospital NHS Trust, Pulmonary Vascular Diseases Unit	Cambridge		United Kingdom	CB23 3RE
35	Hammersmith Hospital	London		United Kingdom	W12 0HS
36	Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital, Pulmonary Vascular Medicine	Sheffield		United Kingdom	S10 2RX

Sponsors and Collaborators

• Actelion

Investigators

• Study Chair: Kelly Papadakis, MD, Actelion

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT02021292
• Other Study ID Numbers: AC-055E201
• First Posted: Dec 27, 2013
• Last Update Posted: Jun 4, 2020
• Last Verified: May 1, 2020

• Keywords provided by Actelion: Chronic thromboembolic pulmonary hypertension (CTEPH)
• Additional relevant MeSH terms: Hypertension, Pulmonary; Hypertension; Macitentan

Study Results

Participant Flow

Recruitment Details	A total of 48 sites in 20 countries screened subjects for recruitment. The study was conducted (i.e., randomized subjects) in a total of 36 sites across 16 countries: Belgium, China, Czech Republic, France, Germany, Hungary, Lithuania, Mexico, Poland, Russia, Thailand, Turkey, South Korea, Switzerland, Ukraine, and the United Kingdom).
Pre-assignment Detail	Target screening period from Visit 1 up to Randomization was maximum of 30 days, but longer period (up to 60 days) was permitted with pre-approval from Actelion. Total of 186 subjects were screened. Of these, 80 subjects were randomized in 1:1 ratio to macitentan 10 milligram (mg) (n = 40) and placebo (n = 40). All randomized subjects were treated.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily.	Matching placebo oral tablet, to be taken once daily.
Period Title: Overall Study
STARTED	40	40
COMPLETED	40	37
NOT COMPLETED	0	3

Baseline Characteristics

Arm/Group Title	Macitentan	Placebo	Total
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily.	Matching placebo oral tablet, to be taken once daily.	Total of all reporting groups
Overall Participants	40	40	80
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	26 65%	26 65%	52 65%
>=65 years	14 35%	14 35%	28 35%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60.0	58.0	59.0
Sex: Female, Male (Count of Participants)
Female	26 65%	25 62.5%	51 63.8%
Male	14 35%	15 37.5%	29 36.3%
Region of Enrollment (Count of Participants)
Asia	15 37.5%	14 35%	29 36.3%
Eastern Europe	17 42.5%	19 47.5%	36 45%
Latin America	1 2.5%	1 2.5%	2 2.5%
Western Europe	7 17.5%	6 15%	13 16.3%
Body Mass Index (BMI) (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	25.7	26.0	25.7
Time since diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.7 (2.36)	1.2 (1.95)	1.5 (2.16)
6-minute walk distance (6MWD) (meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meter]	353.0 (87.90)	351.2 (73.79)	352.1 (80.64)
Pulmonary vascular resistance (PVR) (dynes*sec/cm^5) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [dynes*sec/cm^5]	929.2 (379.65)	984.3 (487.06)	956.8 (434.78)
WHO functional class (Count of Participants)
class I	0 0%	0 0%	0 0%
class II	12 30%	6 15%	18 22.5%
class III	28 70%	33 82.5%	61 76.3%
class IV	0 0%	1 2.5%	1 1.3%
Use of pulmonary arterial hypertension (PAH) medication (Count of Participants)
NO	16 40%	15 37.5%	31 38.8%
YES	24 60%	25 62.5%	49 61.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest.
Description	The primary efficacy endpoint is defined as the PVR at rest at Week 16 expressed as percent of baseline PVR at rest.
Time Frame	From baseline to Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set included all subjects assigned to a study treatment.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily	Matching placebo oral tablet, to be taken once daily
Measure Participants	40	40
Geometric Mean (95% Confidence Interval) [percent of baseline PVR]	73.0	87.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments	The null hypothesis (change of PVR at rest in Week 16 in percent of baseline PVR in subjects treated with placebo or macitentan is the same) is tested on the primary endpoint by means of an analysis of covariance (ANCOVA) model on the log(e) transformed % of baseline PVR at rest at Week 16.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0410
	Comments
	Method	ANCOVA
	Comments	ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate.
Method of Estimation	Estimation Parameter	ratio of geometric means
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.70 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD).
Description	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.
Time Frame	From baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily.	Matching placebo oral tablet, to be taken once daily.
Measure Participants	40	40
6MWD (m) at baseline	353.0 (87.90)	351.2 (73.79)
6MWD (m) at Week 24	388.0 (83.31)	352.2 (121.29)
Change in 6MWD (m) from baseline to Week 24	35.0 (52.52)	1.0 (83.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments	The null hypothesis is that the mean change from baseline in 6MWD at Week 24 is the same in the placebo and the macitentan group. Statistical model is ANCOVA including 6MWD at baseline as a covariate, with treatment as factor in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0326
	Comments	To control multiplicity across all endpoints, secondary endpoints were analyzed in sequence using hierarchical approach based on order and significance as pre-specified in protocol eliminating further adjustment for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	least squares (LS) mean difference
	Estimated Value	34.04
	Confidence Interval	(2-Sided) 95%; 2.9 to 65.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT).
Description	This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 24 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.
Time Frame	From baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily.	Matching placebo oral tablet, to be taken once daily.
Measure Participants	40	40
Borg dyspnea index score at baseline	4.2 (2.52)	4.2 (2.14)
Borg dyspnea index score at Week 24	4.1 (2.52)	4.4 (2.45)
Change from baseline to Week 24	-0.1 (1.86)	0.3 (2.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments	The null hypothesis is that the mean change from baseline is the same in the placebo and the macitentan group. Statistical model is Analysis of Covariance including Borg dyspnea index at baseline as a covariate, with Treatment as factor in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3492
	Comments	To control multiplicity across all endpoints, secondary endpoints were analyzed in sequence using hierarchical approach based on order and significance as pre-specified in protocol eliminating further adjustment for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	least squares (LS) mean difference
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -1.21 to 0.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24
Description	WHO functional classes are defined as follows: 1) class I: no symptoms with exercise or at rest. No limitation of activity. 2) 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). 3) class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. 4) class IV: symptoms at rest (such as dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms (e.g. may faint especially while bending over with their heads lowered). Patients in class IV manifest signs of right heart failure. Shifting to a higher class (e.g. from class III to class IV) represents a 'worsening' while shifting to a lower class (e.g. from class III to class II) means an 'improvement'.
Time Frame	From baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily.	Matching placebo oral tablet, to be taken once daily.
Measure Participants	40	40
WHO functional class I at baseline	0 0%	0 0%
WHO functional class II at baseline	12 30%	6 15%
WHO functional class III at baseline	28 70%	33 82.5%
WHO functional class IV at baseline	0 0%	1 2.5%
WHO functional class I at Week 24	3 7.5%	1 2.5%
WHO functional class II at Week 24	15 37.5%	10 25%
WHO functional class III at Week 24	22 55%	26 65%
WHO functional class IV at Week 24	0 0%	3 7.5%
Worsened	0 0%	3 7.5%
Not worsened - total	40 100%	37 92.5%
Not Worsened - unchanged	31 77.5%	29 72.5%
Not worsened - improved	9 22.5%	8 20%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments	The null hypothesis is the odds of worsening are the same in the placebo and the macitentan group. Logistic regression is used for Treatment Group vs. Placebo comparison to generate odds ratio, confidence levels, and p-values with treatment and WHO functional class at baseline as factors in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0962
	Comments	To control multiplicity across all endpoints, secondary endpoints were analyzed in sequence using hierarchical approach based on order and significance as pre-specified in protocol eliminating further adjustment for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.212
	Confidence Interval	(2-Sided) 95%; 0.001 to 1.464
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Post-Hoc Outcome

Title	Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Including Subjects With Corrected Hemodynamic Values
Description	The main analysis of the primary efficacy endpoint of PVR was repeated after the voluntary right heart catheterization source data verification (SDV) and independent medical review of hemodynamic data corrected for 13 subjects reported after the clinical database closure.
Time Frame	From baseline to Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set for this post-hoc analysis included all subjects assigned to a study treatment with SDV values.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily.	Matching placebo oral tablet, to be taken once daily.
Measure Participants	40	40
Geometric Mean (95% Confidence Interval) [Percent of baseline PVR]	71.5	87.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments	The same statistical model as for the predefined analysis (ANCOVA) was applied, including 13 subjects with corrected hemodynamic values.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0098
	Comments	This is the post-hoc analysis and p-value is an exploratory p-value.
	Method	ANCOVA
	Comments	ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate.
Method of Estimation	Estimation Parameter	Model-adjusted geometric mean ratio
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.70 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Post-Hoc Outcome

Title	Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Corrected Hemodynamic Values
Description	The main analysis of the primary efficacy endpoint of PVR was repeated which excluded data for 13 subjects with corrected hemodynamic values. The hemodynamic values were reported after the SDV assessment clinical database closure.
Time Frame	From baseline to Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set excluding subjects with corrected hemodynamic values.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily.	Matching placebo oral tablet, to be taken once daily.
Measure Participants	33	34
Geometric Mean (95% Confidence Interval) [Percent of baseline PVR]	68.4	86.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0061
	Comments	This is the post-hoc analysis and p-value is an exploratory p-value.
	Method	ANCOVA
	Comments	ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate.
Method of Estimation	Estimation Parameter	Model-adjusted geometric mean ratio
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.68 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Post-Hoc Outcome

Title	Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Implausible Hemodynamic Findings
Description	The main analysis of the primary efficacy endpoint of PVR was repeated which excluded 14 subjects with implausible hemodynamic findings.
Time Frame	From baseline to Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set excluding subjects with implausible hemodynamic findings.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily.	Matching placebo oral tablet, to be taken once daily.
Measure Participants	32	34
Geometric Mean (95% Confidence Interval) [Percent of baseline PVR]	73.9	86.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0414
	Comments	This is the post-hoc analysis and p-value is an exploratory p-value.
	Method	ANCOVA
	Comments	ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate.
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.73 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Post-Hoc Outcome

Title	Post-hoc Analysis of Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD) Excluding Subjects With Implausible Hemodynamic Findings
Description	The same analysis for the secondary endpoint, 6MWD, is repeated on the full analysis set excluding 14 subjects with implausible hemodynamic findings.
Time Frame	From baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set excluding subjects with implausible hemodynamic findings.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily.	Matching placebo oral tablet, to be taken once daily.
Measure Participants	32	34
Least Squares Mean (95% Confidence Interval) [meter]	37.41	0.23

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0468
	Comments	This is the post-hoc analysis and p-value is an exploratory p-value.
	Method	ANCOVA
	Comments	Statistical model is ANCOVA including 6MWD at baseline as a covariate, with treatment as factor in the model.
Method of Estimation	Estimation Parameter	least squares (LS) mean difference
	Estimated Value	37.19
	Confidence Interval	(2-Sided) 95%; 0.54 to 73.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From double-blind study treatment initiation up to 30 days after study treatment discontinuation
Arm/Group Title	Macitentan		Placebo
Arm/Group Description	Macitentan 10 mg, oral tablet, to be taken once daily.		Matching placebo oral tablet, to be taken once daily.
All Cause Mortality
	Macitentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		2/40 (5%)
Serious Adverse Events
	Macitentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/40 (7.5%)		7/40 (17.5%)
Cardiac disorders
Acute right ventricular failure	1/40 (2.5%)	1	0/40 (0%)	0
Cardiac failure	0/40 (0%)	0	1/40 (2.5%)	2
Right ventricular failure	0/40 (0%)	0	2/40 (5%)	2
Supraventricular tachycardia	0/40 (0%)	0	1/40 (2.5%)	1
General disorders
Oedema peripheral	1/40 (2.5%)	1	0/40 (0%)	0
Infections and infestations
Sepsis	0/40 (0%)	0	1/40 (2.5%)	1
Investigations
Weight increased	1/40 (2.5%)	1	0/40 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/40 (0%)	0	1/40 (2.5%)	1
Nervous system disorders
Haemorrhagic stroke	0/40 (0%)	0	1/40 (2.5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/40 (0%)	0	1/40 (2.5%)	1
Pulmonary hypertension	0/40 (0%)	0	2/40 (5%)	2
Vascular disorders
Embolism	0/40 (0%)	0	1/40 (2.5%)	1
Other (Not Including Serious) Adverse Events
	Macitentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/40 (55%)		19/40 (47.5%)
Cardiac disorders
Ventricular extrasystoles	0/40 (0%)	0	2/40 (5%)	2
General disorders
Fatigue	2/40 (5%)	2	0/40 (0%)	0
Oedema peripheral	8/40 (20%)	10	4/40 (10%)	4
Infections and infestations
Nasopharyngitis	1/40 (2.5%)	1	4/40 (10%)	4
Pharyngitis	2/40 (5%)	3	0/40 (0%)	0
Respiratory tract infection	0/40 (0%)	0	2/40 (5%)	2
Upper respiratory tract infection	3/40 (7.5%)	4	0/40 (0%)	0
Urinary tract infection	2/40 (5%)	2	1/40 (2.5%)	1
Investigations
Alanine aminotransferase increased	0/40 (0%)	0	3/40 (7.5%)	4
Aspartate aminotransferase increased	0/40 (0%)	0	3/40 (7.5%)	4
Haemoglobin decreased	6/40 (15%)	7	0/40 (0%)	0
Metabolism and nutrition disorders
Hypomagnesaemia	0/40 (0%)	0	2/40 (5%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/40 (2.5%)	1	3/40 (7.5%)	3
Back pain	0/40 (0%)	0	2/40 (5%)	2
Bone pain	2/40 (5%)	3	0/40 (0%)	0
Pain in extremity	3/40 (7.5%)	3	0/40 (0%)	0
Nervous system disorders
Dizziness	2/40 (5%)	2	1/40 (2.5%)	1
Syncope	0/40 (0%)	0	3/40 (7.5%)	3
Respiratory, thoracic and mediastinal disorders
Cough	2/40 (5%)	2	3/40 (7.5%)	3
Dyspnoea	2/40 (5%)	2	1/40 (2.5%)	1
Epistaxis	1/40 (2.5%)	1	2/40 (5%)	2
Pulmonary hypertension	0/40 (0%)	0	2/40 (5%)	2
Vascular disorders
Hypotension	0/40 (0%)	0	2/40 (5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Any study-related publication written independently by investigators must be submitted to Actelion for review at least 30 days prior to submission for publication or presentation. Upon review, Actelion may provide comments, and may also request alterations and/or deletions for the sole purpose of protecting its confidential information and/or patent rights.