MELODY-1: Clinical Study to Evaluate the Safety and Tolerability of Macitentan in Subjects With Combined Pre- and Post-capillary Pulmonary Hypertension (CpcPH) Due to Left Ventricular Dysfunction

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02070991
• Collaborator: (none)
• Enrollment: 63
• Locations: 32
• Arms: 2
• Actual Duration (Months): 16
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Study to evaluate if macitentan is safe and tolerable enough to be used for treatment of subjects with combined pre- and post-capillary pulmonary hypertension (CpcPH) due to left ventricular dysfunction.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Prospective, Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group, 12-week Study to Evaluate the Safety and Tolerability of Macitentan in Subjects With Combined Pre- and Post-capillary Pulmonary Hypertension (CpcPH) Due to Left Ventricular Dysfunction
• Actual Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment [From randomization up to End-of-Study (Week 12 + 30 days follow-up) plus 1 calendar day]

   The main endpoint is the number of participants who had at least one of the following: A) significant fluid retention, defined as increase in body weight at any time by ≥ 5% or ≥ 5 kg from baseline due to fluid overload and/or parenteral administration of diuretics. B) Worsening of NYHA functional class from baseline.

Secondary Outcome Measures

1. NT-proBNP at Week 12 Expressed as Percent of Baseline NT-proBNP at Rest [From randomization up to end of treatment period (Week 12)]

2. PVR at Rest at Week 12 Expressed as Percent of Baseline PVR at Rest [From randomization up to end of treatment period (Week 12)]

   Pulmonary vascular resistance (PVR) was assessed at rest by right heart catheterization (RHC).

3. Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) [From randomization up to end of treatment period (Week 12)]

4. Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) [From randomization up to end of treatment period (Week 12)]

5. Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP) [From randomization up to end of treatment period (Week 12)]

6. Change From Baseline to Week 12 in Cardiac Index (CI) [From randomization up to end of treatment period (Week 12)]

7. Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG) [From randomization up to end of treatment period (Week 12)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males and Females >=18 years of age

2. Subjects with combined pre-and post-capillary Pulmonary Hypertension (CpcPH) due to left ventricular dysfunction (subset of WHO groups 2.1 and 2.2)

3. Optimized diuretic therapy

Exclusion Criteria:

1. Types of Pulmonary Hypertension other than WHO groups 2.1 and 2.2 (Nice classification)

2. Administration of PAH-specific therapy (i.e., Endothelin receptor antagonists (ERAs), Prostanoids, Phosphodiesterase 5 (PDE-5) inhibitors, guanylate cyclase stimulators)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kentuckiana Pulmonary Associates	Louisville	Kentucky	United States	40202
2	Boston University School of Medicine	Boston	Massachusetts	United States	02118
3	University of Michigan Internal Medicine Cardiology, Pulmonary Hypertension Program	Ann Arbor	Michigan	United States	48109
4	Washington University School of Medicine - Center for Advanced Med	Saint Louis	Missouri	United States
5	The Lindner Clinical Trial Center	Cincinnati	Ohio	United States
6	Houston Methodist Hospital - Heart Failure/Pulm Hypertension	Houston	Texas	United States
7	Krankenhaus der Elisabethinen Linz, 2. Interne Abteilung	Linz		Austria
8	Medical University of Vienna and AKH Cardiology	Vienna		Austria	A-1090
9	Hôpital Erasme, Cliniques Universitaires de Bruxelles, Cardiologie	Brussels		Belgium	1070
10	University Hospital Gasthuisberg / Interne Geneeskunde - I.G. Pneumologie	Leuven		Belgium	3000
11	Vancouver General Hospital - The Lung	Vancouver		Canada
12	FN Brno-Bohunice, I. interní kardiologická klinika	Brno		Czechia
13	FN Olomouc, 1. Interní klinika - kardiologická	Olomouc		Czechia
14	IKEM (Institut klinické a experimentální medicíny, Institute for Clinical and Experimental Medicine)	Praha		Czechia
15	Lékařská fakulta a Všeobecná fakultní nemocnice v Praze, II. Interní klinika kardiologie a angiologie	Praha		Czechia
16	Hôpital Charles Nicolle Service de Cardiologie	Rouen cedex		France
17	DRK Klinken Berlin Kopenick Klinik für Innere Medizin Kardiologie	Berlin		Germany
18	Universitätsklinik Schleswig-Holstein Campus Kiel Klinik für Innere Medizin III Kardiologie und Angiologie	Kiel		Germany
19	Universitätsklinikum Köln Herzzentrum / Klinik III für Innere Medizin (Kardiologie, Pneumologie, Angiologie und Intensivmedizin)	Köln		Germany
20	Klinikum der Universität München Medizinische Klinik und Poliklinik 1 - Großhadern Schwerpunkt Pneumologie	Munich		Germany
21	Carmel Medical Center, Pulmonary Unit	Haifa		Israel	34362
22	Institute of Pulmonology Hadassah Medical Centre : Ein Karem	Jerusalem		Israel	91120
23	Kaplan Medical Centre / Pulmonary Institute and Department of Medicine	Rehovot		Israel	76100
24	The Chaim Sheba Medical Center / The Institute of Pulmonology, Physiology and Exercise	Tel-Hashomer		Israel	52621
25	A.O. Universitaria Policlinico S. Orsola-Malpighi - Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale - Unità Operativa di Cardiologia	Bologna		Italy	40138
26	Ospedali Riuniti Di Trieste	Trieste		Italy	34149
27	Hospital Vall d´Hebron Servicio de Cardiologia	Barcelona		Spain	08035
28	Hospital Clinic Servicio de Cardiologia	Barcelona		Spain	08036
29	Hospital Reina Sofia Servicio de Cardiologia	Cordoba		Spain	14004
30	Hospital Universitario 12 Octubre Servicio de Cardiología	Madrid		Spain	28041
31	Universitätsklinik für Kardiologie Schweizer Herz- und Gefässzentrum Bern	Bern		Switzerland
32	Centre Hospitalier Universitaire Vaudois Service de Cardiologie	Lausanne		Switzerland

Sponsors and Collaborators

• Actelion

Investigators

• Study Chair: Sébastien Roux, PhD, Actelion

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT02070991
• Other Study ID Numbers: AC-055G201
• First Posted: Feb 25, 2014
• Last Update Posted: May 15, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by Actelion: pre- and post-capillary pulmonary hypertension; CpcPH
• Additional relevant MeSH terms: Hypertension, Pulmonary; Hypertension; Ventricular Dysfunction; Ventricular Dysfunction, Left; Macitentan

Study Results

Participant Flow

Recruitment Details	Participants were screened from 28 sites across Europe and North America in 11 countries (Austria, Belgium, Canada, Czech Republic, Germany, France, Israel, Italy, Spain, Switzerland, USA).
Pre-assignment Detail	Of the 88 participants screened 63 were randomized in a 1:1 ratio to macitentan 10 mg (N = 31) or placebo (N = 32).

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet	Matching placebo to be taken once daily, oral use, film-coated tablet
Period Title: Overall Study
STARTED	31	32
COMPLETED	28	32
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	Macitentan	Placebo	Total
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet	Matching placebo to be taken once daily, oral use, film-coated tablet	Total of all reporting groups
Overall Participants	31	32	63
Age (Years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Years]	70.0	72.0	71.0
Age, Customized (Count of Participants)
18-64 years	5 16.1%	3 9.4%	8 12.7%
65-84 years	26 83.9%	28 87.5%	54 85.7%
≥ 85 years	0 0%	1 3.1%	1 1.6%
Sex: Female, Male (Count of Participants)
Female	25 80.6%	16 50%	41 65.1%
Male	6 19.4%	16 50%	22 34.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.2%	1 3.1%	2 3.2%
Not Hispanic or Latino	30 96.8%	31 96.9%	61 96.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	0 0%	1 3.1%	1 1.6%
American Indian or Alaska Native	1 3.2%	0 0%	1 1.6%
White	30 96.8%	30 93.8%	60 95.2%
Other	0 0%	1 3.1%	1 1.6%
Time from Left Ventricular Dysfunction (LVD) diagnosis (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	0.9	1.5	1.3
Time from Combined pre- and post-capillary Pulmonary Hypertension (CpcPH) diagnosis (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	0.2	0.2	0.2
New York Heart Association (NYHA) Functional Class at baseline (Count of Participants)
Class I	0 0%	0 0%	0 0%
Class II	5 16.1%	10 31.3%	15 23.8%
Class III	26 83.9%	22 68.8%	48 76.2%
Class IV	0 0%	0 0%	0 0%
6-minute walk distance (6MWD) at baseline (meter) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [meter]	300.0	305.0	300.0
Participants with Atrial Fibrillation at baseline (Count of Participants)
Yes	22 71%	24 75%	46 73%
No	9 29%	8 25%	17 27%
Participants with Diabetes Mellitus Type II (Count of Participants)
Yes	14 45.2%	13 40.6%	27 42.9%
No	17 54.8%	19 59.4%	36 57.1%
Participants with Right Heart Failure (RHF) (Count of Participants)
Yes	7 22.6%	11 34.4%	18 28.6%
No	24 77.4%	21 65.6%	45 71.4%
Participants with Systemic Hypertension (Count of Participants)
Yes	30 96.8%	27 84.4%	57 90.5%
No	1 3.2%	5 15.6%	6 9.5%
Participants with Chronic Kidney Disease (CKD) (Count of Participants)
Yes	8 25.8%	6 18.8%	14 22.2%
No	23 74.2%	26 81.3%	49 77.8%
Left Ventricular Ejection Fraction (LEVF) at baseline as measured by Investigator (Count of Participants)
< 50%	6 19.4%	9 28.1%	15 23.8%
≥ 50%	25 80.6%	23 71.9%	48 76.2%
Pulmonary Vascular Resistance (PVR) at baseline (dyn*sec/cm^5) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [dyn*sec/cm^5]	450.0	483.5	462.0
Body Mass Index (BMI) at baseline (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	33.30	31.15	32.40
Participants with obesity (BMI > 30 kg/m^2) (Count of Participants)
Yes	20 64.5%	20 62.5%	40 63.5%
No	11 35.5%	12 37.5%	23 36.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment
Description	The main endpoint is the number of participants who had at least one of the following: A) significant fluid retention, defined as increase in body weight at any time by ≥ 5% or ≥ 5 kg from baseline due to fluid overload and/or parenteral administration of diuretics. B) Worsening of NYHA functional class from baseline.
Time Frame	From randomization up to End-of-Study (Week 12 + 30 days follow-up) plus 1 calendar day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet	Matching placebo to be taken once daily, oral use, film-coated tablet
Measure Participants	31	32
Total participants with at least one condition	7 22.6%	4 12.5%
Participants with fluid retention	7 22.6%	3 9.4%
Participants with worsening in NYHA FC	1 3.2%	2 6.3%
Participants with both conditions	1 3.2%	1 3.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3372
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference between maci. and placebo
	Estimated Value	10.08
	Confidence Interval	(2-Sided) 95%; -15.07 to 33.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	NT-proBNP at Week 12 Expressed as Percent of Baseline NT-proBNP at Rest
Time Frame	From randomization up to end of treatment period (Week 12)

Outcome Measure Data

Analysis Population Description

The values of 6 patients are missing in both the macitentan and the placebo group.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet	Matching placebo to be taken once daily, oral use, film-coated tablet
Measure Participants	25	26
Geometric Mean (95% Confidence Interval) [percentage of baseline NT-proBNP]	91.56	118.90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (ratio of geom. means)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.55 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	PVR at Rest at Week 12 Expressed as Percent of Baseline PVR at Rest
Description	Pulmonary vascular resistance (PVR) was assessed at rest by right heart catheterization (RHC).
Time Frame	From randomization up to end of treatment period (Week 12)

Outcome Measure Data

Analysis Population Description

The values of 11 patients in the macitentan group and of 8 patients in the placebo group are missing.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet	Matching placebo to be taken once daily, oral use, film-coated tablet
Measure Participants	20	24
Geometric Mean (95% Confidence Interval) [percentage of baseline PVR]	66.31	71.23

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (ratio of geom. means)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP)
Time Frame	From randomization up to end of treatment period (Week 12)

Outcome Measure Data

Analysis Population Description

The values of 10 patients in the macitentan group and of 7 patients in the placebo group are missing.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet	Matching placebo to be taken once daily, oral use, film-coated tablet
Measure Participants	21	25
mPAP at baseline	44.6	45.9
mPAP at Week 12	41.1	42.1
Change in mPAP from baseline to Week 12	-3.5	-3.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (mean change from BL)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -4.3 to 4.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)
Time Frame	From randomization up to end of treatment period (Week 12)

Outcome Measure Data

Analysis Population Description

The values of 10 patients in the macitentan group and of 7 patients in the placebo group are missing.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet	Matching placebo to be taken once daily, oral use, film-coated tablet
Measure Participants	21	25
mRAP at baseline	12.1	13.0
mRAP at Week 12	11.2	11.3
Change in mRAP from baseline to Week 12	-0.9	-1.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (mean change from BL)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -2.2 to 3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP)
Time Frame	From randomization up to end of treatment period (Week 12)

Outcome Measure Data

Analysis Population Description

The values of 11 patients in the macitentan group and of 8 patients in the placebo group are missing.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet	Matching placebo to be taken once daily, oral use, film-coated tablet
Measure Participants	20	24
PAWP at baseline	19.1	19.7
PAWP at Week 12	19.9	20.8
Change in PAWP from baseline to Week 12	0.8	1.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (mean change from BL)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -4.2 to 3.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline to Week 12 in Cardiac Index (CI)
Time Frame	From randomization up to end of treatment period (Week 12)

Outcome Measure Data

Analysis Population Description

The values of 11 patients in the macitentan group and of 8 patients in the placebo group are missing.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet	Matching placebo to be taken once daily, oral use, film-coated tablet
Measure Participants	20	24
CI at baseline	2.32	2.33
CI at Week 12	2.69	2.30
Change in CI from baseline to Week 12	0.37	-0.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (mean change from BL)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.11 to 0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG)
Time Frame	From randomization up to end of treatment period (Week 12)

Outcome Measure Data

Analysis Population Description

The values of 11 patients in the macitentan group and of 8 patients in the placebo group are missing.

Arm/Group Title	Macitentan	Placebo
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet	Matching placebo to be taken once daily, oral use, film-coated tablet
Measure Participants	20	24
DPG at baseline	11.8	11.4
DPG at Week 12	7.0	7.0
Change in DPG from baseline to Week 12	-4.8	-4.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (mean change from BL)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -4.5 to 3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From study treatment initiation up to 30 days after study treatment discontinuation (Week 12 + 30 days)
Arm/Group Title	Macitentan		Placebo
Arm/Group Description	Macitentan 10 mg to be taken once daily, oral use, film-coated tablet		Matching placebo to be taken once daily, oral use, film-coated tablet
All Cause Mortality
	Macitentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/31 (6.5%)		0/32 (0%)
Serious Adverse Events
	Macitentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/31 (35.5%)		6/32 (18.8%)
Cardiac disorders
Atrial fibrillation	0/31 (0%)	0	1/32 (3.1%)	1
Cardiac failure acute	1/31 (3.2%)	1	0/32 (0%)	0
Cardiac failure congestive	1/31 (3.2%)	1	1/32 (3.1%)	1
Cardiorenal syndrome	1/31 (3.2%)	1	0/32 (0%)	0
Left ventricular failure	1/31 (3.2%)	1	0/32 (0%)	0
Right ventricular failure	1/31 (3.2%)	1	1/32 (3.1%)	1
Ventricular tachycardia	1/31 (3.2%)	1	0/32 (0%)	0
Gastrointestinal disorders
Mouth haemorrhage	1/31 (3.2%)	1	0/32 (0%)	0
General disorders
Oedema peripheral	1/31 (3.2%)	1	1/32 (3.1%)	1
Sudden death	1/31 (3.2%)	1	0/32 (0%)	0
Infections and infestations
Pneumonia	2/31 (6.5%)	2	0/32 (0%)	0
Respiratory tract infection bacterial	1/31 (3.2%)	1	0/32 (0%)	0
Injury, poisoning and procedural complications
Fall	0/31 (0%)	0	1/32 (3.1%)	2
Metabolism and nutrition disorders
Hypoglycaemia	1/31 (3.2%)	1	0/32 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/31 (0%)	0	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Chronic respiratory failure	1/31 (3.2%)	1	0/32 (0%)	0
Pulmonary congestion	1/31 (3.2%)	1	0/32 (0%)	0
Pulmonary mass	1/31 (3.2%)	1	0/32 (0%)	0
Pulmonary oedema	1/31 (3.2%)	1	0/32 (0%)	0
Respiratory failure	1/31 (3.2%)	1	0/32 (0%)	0
Vascular disorders
Jugular vein thrombosis	1/31 (3.2%)	1	0/32 (0%)	0
Other (Not Including Serious) Adverse Events
	Macitentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/31 (51.6%)		15/32 (46.9%)
Blood and lymphatic system disorders
Anaemia	2/31 (6.5%)	2	0/32 (0%)	0
Cardiac disorders
Atrial fibrillation	1/31 (3.2%)	1	2/32 (6.3%)	2
Mitral valve incompetence	2/31 (6.5%)	2	0/32 (0%)	0
Gastrointestinal disorders
Diarrhoea	3/31 (9.7%)	3	1/32 (3.1%)	1
Nausea	1/31 (3.2%)	1	2/32 (6.3%)	2
General disorders
Fatigue	0/31 (0%)	0	2/32 (6.3%)	2
Oedema peripheral	2/31 (6.5%)	2	3/32 (9.4%)	3
Infections and infestations
Respiratory tract infection	2/31 (6.5%)	2	0/32 (0%)	0
Urinary tract infection	0/31 (0%)	0	2/32 (6.3%)	3
Investigations
Blood bilirubin increased	0/31 (0%)	0	2/32 (6.3%)	2
Haemoglobin decreased	2/31 (6.5%)	2	0/32 (0%)	0
Walking distance test abnormal	0/31 (0%)	0	2/32 (6.3%)	2
Metabolism and nutrition disorders
Fluid retention	2/31 (6.5%)	3	0/32 (0%)	0
Hypokalaemia	2/31 (6.5%)	2	0/32 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic neoplasm	2/31 (6.5%)	2	0/32 (0%)	0
Nervous system disorders
Dizziness	2/31 (6.5%)	2	0/32 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/31 (3.2%)	1	2/32 (6.3%)	2
Dyspnoea	3/31 (9.7%)	4	4/32 (12.5%)	5
Pleural effusion	0/31 (0%)	0	2/32 (6.3%)	3

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.