REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02310672
• Collaborator: (none)
• Enrollment: 89
• Locations: 41
• Arm: 1
• Actual Duration (Months): 51.3
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The study evaluates the effect of macitentan on right ventricular and hemodynamic properties in patients with symptomatic pulmonary arterial hypertension. Patients are treated with macitentan for 1 year. Patients undergo right heart catheterization (RHC) at baseline and Week 26. They also undergo cardiac magnetic resonance imaging (MRI) at baseline, Week 26 and Week 52. Safety is monitored throughout the study. The study has three stub-studies. Each patient can participate in no sub-study or in one sub-study. The sub-studies are: (1) metabolism sub-study (with PET-MR scans); (2) biopsy sub-study (biopsies taken during the RHC); (3) Echo sub-study.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Macitentan	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Multicenter, Single-arm, Open-label, Phase 4 Study to Evaluate the Effects of Macitentan on Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension Assessed by Cardiac Magnetic Resonance Imaging
• Actual Study Start Date: Jun 1, 2015
• Actual Primary Completion Date: Sep 10, 2019
• Actual Study Completion Date: Sep 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Macitentan All patients take open-label macitentan 10mg o.d.	Drug: Macitentan; All patients take open-label macitentan 10mg o.d.; Other Names: ACT-064992

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Right Ventricular Stroke Volume (RVSV) to Week 26 [Baseline and Week 26]

   Change from baseline in RVSV assessed by cardiac magnetic resonance imaging (MRI) from pulmonary artery flow was reported at Week 26. Primary analysis were based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is.

2. Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR) [Baseline and Week 26]

   Ratio of Week 26 to baseline PVR as assessed by RHC was reported. PVR represents the resistance against which the right ventricle needs to pump. PVR is determined by right heart catheterization (RHC). PVR was calculated as 80*(Mean pulmonary arterial pressure [mPAP] -[Pulmonary capillary wedge pressure {PCWP} or Left ventricular end diastolic pressure {LVEDP} if PCWP not available/cardiac output [CO]). Primary analysis were based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is.

Secondary Outcome Measures

1. Change From Baseline in Right Ventricular End Diastolic Volume (RVEDV) to Week 26 [Baseline to Week 26]

   Change from baseline to Week 26 in RVEDV assessed by cardiac MRI was reported.

2. Change From Baseline in Right Ventricular End Systolic Volume (RVESV) to Week 26 [Baseline to Week 26]

   Change from baseline to Week 26 in RVESV assessed by cardiac MRI was reported.

3. Change From Baseline in Right Ventricular Ejection Fraction (RVEF) to Week 26 (% Blood Volume) [Baseline to Week 26]

   Change from baseline to Week 26 in RVEF based on pulmonary artery flow assessed by cardiac MRI was reported.

4. Change From Baseline in Right Ventricle (RV) Mass to Week 26 [Baseline to Week 26]

   Change from baseline to Week 26 in RV mass assessed by cardiac MRI was reported.

5. Change From Baseline in Six-minutes Walk Distance (6MWD) to Week 26 [Baseline to Week 26]

   6MWD is a non-encouraged test performed in a 30 meter (m) long flat corridor, where the participant is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. This test is used to assess exercise capacity. The test was performed about 30 minutes after study drug administration. Any increase in the walk distance was considered improvement from baseline.

6. Change From Baseline in World Health Organization Functional Class (WHO FC) to Week 26 [Baseline to Week 26]

   WHO FC is a classification which reflects disease severity based on symptoms. WHO Functional Classification of pulmonary hypertension comprises of Class I (participants with pulmonary hypertension but without resulting limitation of physical activity), II (participants with pulmonary hypertension resulting in slight limitation of physical activity), III (participants with pulmonary hypertension resulting in marked limitation of physical activity) and IV (participants with pulmonary hypertension with inability to carry out any physical activity without symptoms). Changes from baseline to Week 26 included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or unchanged/stable (same FC at baseline and at the post-baseline time point).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Signed informed consent prior to any study-mandated procedure

2. Symptomatic pulmonary arterial hypertension (PAH)

3. World Health Organization (WHO) Functional Class (FC) I to III

4. PAH etiology belonging to one of the following groups according to Nice classification:

• Idiopathic PAH

• Heritable PAH

• Drug- and toxin-induced PAH

• PAH associated with congenital heart diseases: only simple (atrial septal defect, ventricular septal defect, patent ductus arteriosus) congenital systemic to pulmonary shunts at least 2 year post surgical repair

1. Hemodynamic diagnosis of PAH confirmed by right heart catheterization (RHC) during screening showing:

• mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and

• PCWP (pulmonary capillary wedge pressure) or left ventricular end diastolic pressure (LVEDP) ≤ 12 mmHg and pulmonary vascular resistance (PVR) ≥ 4 Wood Units (WU) (320 dyn.sec.cm-5) or

• 12 mmHg ≤ PCWP or LVEDP ≤ 15 mmHg and PVR ≥ 6WU (480 dyn.sec.cm-5)

1. 6-minute walk distance (6MWD) ≥ 150 m during screening

2. For patients treated with oral diuretics, treatment dose must have been stable at least 1 month prior to RHC during the screening period

3. For patients treated with phosphodiesterase type-5 (PDE-5) inhibitors, treatment dose must have been stable at least 3 months prior to RHC during the screening period

4. For patients treated with beta blockers, treatment dose must have been stable at least 1 month prior to the RHC during the screening period

5. Men or women ≥18 and < 65 years

6. Women of childbearing potential (defined in protocol) must:

• Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and

• Agree to use reliable methods of contraception (defined in protocol) from screening up to 30 days after study treatment discontinuation, and

• Agree to perform monthly pregnancy tests up to 30 days after study treatment discontinuation

Exclusion Criteria:

1. Body weight < 40 kg

2. Body mass index (BMI) > 35kg/m2. For patients with 30kg/m2 < BMI < 35kg/m2, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.

3. Pregnancy, breastfeeding or intention to become pregnant during the study

4. Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program

5. Known concomitant life-threatening disease with a life expectancy < 12 months

6. Any condition likely to affect protocol or treatment compliance

7. Hospitalization for PAH within 3 months prior to informed consent signature

8. Left atrial volume indexed for body surface area ≥ 43mL/m2 by echocardiography or cardiac MRI

9. Valvular disease grade 2 or higher

10. History of pulmonary embolism or deep vein thrombosis

11. Documented moderate to severe chronic obstructive pulmonary disease

12. Documented moderate to severe restrictive lung disease

13. Historical evidence of significant coronary artery disease established by:

• History of myocardial infarction or

• More than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or

• Elevation of the ST segment on electrocardiogram or

• History of coronary artery bypass grafting or

• Stable angina

1. Diabetes mellitus

2. Moderate to severe renal insufficiency (calculated creatinine clearance < 60 mL/min/1.73 m2)

3. Cancer

4. Systolic blood pressure < 90 mmHg

5. Severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × upper limit of the normal range (ULN) accompanied by an aspartate aminotransferase (AST) elevation > ULN at Screening.

6. Hemoglobin < 100g/L

7. AST and/or alanine aminotransferase (ALT) > 3× ULN

8. Need for dialysis

9. Responders to acute vasoreactivity test based on medical history

10. Prior use of endothelin receptor antagonists (ERAs), stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogues

11. Treatment with strong inducers of cytochrome P450 isozyme 3A4 (CYP3A4) within 4 weeks prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, phenytoin and St. John's Wort)

12. Treatment with strong inhibitors of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir)

13. Treatment with another investigational drug (planned, or taken within the 3 months prior to study treatment initiation).

14. Hypersensitivity to any ERA or any excipients of the formulation of macitentan (lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, polyvinyl alcohol, polysorbate, titanium dioxide, talc, xanthan gum, and lecithin soya)

15. Claustrophobia

16. Permanent cardiac pacemaker, automatic internal cardioverter

17. Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of infusion device)

18. Atrial fibrillation, multiple premature ventricular or atrial contractions, or any other condition that would interfere with proper cardiac gating during MRI.

19. For patients enrolling in the metabolism sub-study only: glucose intolerance

20. For patients enrolling in the biopsy sub-study only: PAH etiology belonging to Nice classification 1.4.4: PAH associated with congenital heart diseases

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachussetts General Hospital	Boston	Massachusetts	United States	02114
2	University of Minnesota	Minneapolis	Minnesota	United States	55455
3	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
4	Rudgers New Jersey Medical School	New Brunswick	New Jersey	United States	08901
5	Cornell University	New York	New York	United States	10065
6	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
7	University of Texas Southwestern Medical	Dallas	Texas	United States	75390
8	St. Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
9	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
10	Hopital Gabriel Montpied	Clermont-Ferrand		France	63003
11	Hôpital Michallon	La Tronche		France	38700
12	"CHRU de Lille - Hôpital Albert Calmette "	Lille Cedex		France	59037
13	Hopital de Brabois	Nancy		France	54511
14	Hôpital Laennec	Nantes Cedex 01		France	44093
15	Hôpital Pasteur	Nice		France	06002
16	Hôpital Européen Georges-Pompidou	Paris		France	75015
17	Medizinische Klinik und Poliklinik II Universitätsklinik Bonn	Bonn		Germany	53105
18	Thoraxklinik am Universitätsklinikum Heidelberg	Heidelberg		Germany	69126
19	Universitätsklinikum Köln Herzzentrum / Klinik III für Innere Medizin	Köln		Germany	50924
20	Universitätsmedizin der Johannes Gutenberg-Universität Mainz Centrum für Thrombose und Hämostase	Mainz		Germany	55131
21	Grantham Hospital, Cardiac Medical Unit	Hong Kong		Hong Kong	999077
22	Queen Mary Hospital	Hong Kong		Hong Kong	999077
23	United Christian Hospital	Hong Kong		Hong Kong	999077
24	Pulmonology institute, Soroka Medical Center	Beer-Sheva		Israel	84101
25	Shaare Zedek Medical Center	Jerusalem		Israel	9103102
26	Policlinico Sant'Orsola-Malpighi	Bologna		Italy	40138
27	Fondazione IRCCS Policlinico San Matteo Ambulatorio Scompenso Cardiaco e Trapianti	Pavia		Italy	27100
28	Hospital Pulau Pinang	George Town		Malaysia	10990
29	Institut Jantung Negara (National Heart Institute)	Kuala Lumpur		Malaysia	50400
30	VU University Medical Center (VUMC)	Amsterdam		Netherlands	1081 HV
31	Maastricht UMC+	Maastricht		Netherlands	6229
32	St. Antonius Ziekenhuis	Nieuwegein		Netherlands	3435 CM
33	Radboud UMC	Nijmegen		Netherlands	6525 GA
34	Erasmus University medical Center	Rotterdam		Netherlands	3000 CA
35	Russian Cardiology Scientific and Production Complex	Moscow		Russian Federation	121552
36	Almazov Federal North-West Medical Research Centre of Department of Health	Saint Petersburg		Russian Federation	197341
37	National University Hospital - The Heart Institute - Cardiac Department	Singapore		Singapore	119228
38	National Heart Centre (NHC) Singapore	Singapore		Singapore	169609
39	Golden Jubilee National Hospital	Glasgow		United Kingdom	G81 4DY
40	The Royal Free Hospital	London		United Kingdom	NW3 2QG
41	"Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital"	Sheffield		United Kingdom	S10 2JF

Sponsors and Collaborators

• Actelion

Investigators

• Study Director: Loïc Perchenet, Actelion

Study Documents (Full-Text)

• Study Protocol - Nov 8, 2016
• Statistical Analysis Plan - Mar 20, 2018

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT02310672
• Other Study ID Numbers: AC-055-403
• First Posted: Dec 8, 2014
• Last Update Posted: Sep 24, 2020
• Last Verified: Sep 1, 2020

• Keywords provided by Actelion: Pulmonary Arterial Hypertension
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Ventricular Remodeling; Macitentan

Study Results

Participant Flow

Pre-assignment Detail	Total 112 participants were screened out of them 89 participants were enrolled in the study and of which 87 participants received study medication. Two participants who did not receive study treatment were wrongly classified as enrolled by the sites.

Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
Period Title: Overall Study
STARTED	87
COMPLETED	72
NOT COMPLETED	15

Baseline Characteristics

Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
Overall Participants	87
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.9 (14.48)
Sex: Female, Male (Count of Participants)
Female	70 80.5%
Male	17 19.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.1%
Not Hispanic or Latino	72 82.8%
Unknown or Not Reported	14 16.1%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	1 1.1%
American Indian or Alaska Native	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Asian	26 29.9%
White	46 52.9%
Other	0 0%
Unknown or Not Reported	14 16.1%
Region of Enrollment (Count of Participants)
FRANCE	14 16.1%
GERMANY	12 13.8%
ISRAEL	2 2.3%
ITALY	3 3.4%
MALAYSIA	8 9.2%
NETHERLANDS	12 13.8%
RUSSIAN FEDERATION	11 12.6%
SINGAPORE	9 10.3%
UNITED KINGDOM	3 3.4%
UNITED STATES	6 6.9%
Hong Kong	7 8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Right Ventricular Stroke Volume (RVSV) to Week 26
Description	Change from baseline in RVSV assessed by cardiac magnetic resonance imaging (MRI) from pulmonary artery flow was reported at Week 26. Primary analysis were based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

The Modified full analysis set (mFAS) included of all screened participants who received at least one dose of study drug and who had a baseline as well as a post-baseline measurement taken between 16 weeks and 30 weeks of treatment.

Arm/Group Title	Macitanten 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
Measure Participants	42
Least Squares Mean (Standard Error) [milliliters (mL)]	15.17 (2.75)

2. Primary Outcome

Title	Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR)
Description	Ratio of Week 26 to baseline PVR as assessed by RHC was reported. PVR represents the resistance against which the right ventricle needs to pump. PVR is determined by right heart catheterization (RHC). PVR was calculated as 80*(Mean pulmonary arterial pressure [mPAP] -[Pulmonary capillary wedge pressure {PCWP} or Left ventricular end diastolic pressure {LVEDP} if PCWP not available/cardiac output [CO]). Primary analysis were based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

mFAS included of all screened participants who received at least one dose of study drug and who had a baseline as well as a post-baseline measurement taken between 16 weeks and 30 weeks of treatment.

Arm/Group Title	Macitanten 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
Measure Participants	42
Geometric Mean (Geometric Coefficient of Variation) [Ratio]	0.63 (0.11)

3. Secondary Outcome

Title	Change From Baseline in Right Ventricular End Diastolic Volume (RVEDV) to Week 26
Description	Change from baseline to Week 26 in RVEDV assessed by cardiac MRI was reported.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

Safety set included all screened participants who received at least one dose of study drug. Here 'N' (number of participants analyzed) signifies the number of participants evaluable for this outcome measure.

Arm/Group Title	Macitanten 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
Measure Participants	78
Least Squares Mean (95% Confidence Interval) [mL]	-6.22

4. Secondary Outcome

Title	Change From Baseline in Right Ventricular End Systolic Volume (RVESV) to Week 26
Description	Change from baseline to Week 26 in RVESV assessed by cardiac MRI was reported.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

Safety set included all screened participants who received at least one dose of study drug. Here 'N' (number of participants analyzed) signifies the number of participants evaluable for this outcome measure.

Arm/Group Title	Macitanten 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
Measure Participants	78
Least Squares Mean (95% Confidence Interval) [mL]	-16.39

5. Secondary Outcome

Title	Change From Baseline in Right Ventricular Ejection Fraction (RVEF) to Week 26 (% Blood Volume)
Description	Change from baseline to Week 26 in RVEF based on pulmonary artery flow assessed by cardiac MRI was reported.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

Safety set included all screened participants who received at least one dose of study drug. Here 'N' (number of participants analyzed) signifies the number of participants evaluable for this outcome measure.

Arm/Group Title	Macitanten 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
Measure Participants	72
Least Squares Mean (95% Confidence Interval) [Percentage of blood volume]	10.14

6. Secondary Outcome

Title	Change From Baseline in Right Ventricle (RV) Mass to Week 26
Description	Change from baseline to Week 26 in RV mass assessed by cardiac MRI was reported.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

Safety set included all screened participants who received at least one dose of study drug. Here 'N' (number of participants analyzed) signifies the number of participants evaluable for this outcome measure.

Arm/Group Title	Macitanten 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
Measure Participants	78
Least Squares Mean (95% Confidence Interval) [Grams]	-10.10

7. Secondary Outcome

Title	Change From Baseline in Six-minutes Walk Distance (6MWD) to Week 26
Description	6MWD is a non-encouraged test performed in a 30 meter (m) long flat corridor, where the participant is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. This test is used to assess exercise capacity. The test was performed about 30 minutes after study drug administration. Any increase in the walk distance was considered improvement from baseline.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

Safety set included all screened participants who received at least one dose of study drug. Here 'N' (number of participants analyzed) signifies the number of participants evaluable for this outcome measure.

Arm/Group Title	Macitanten 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
Measure Participants	83
Least Squares Mean (Standard Error) [Meters]	38.85 (7.37)

8. Secondary Outcome

Title	Change From Baseline in World Health Organization Functional Class (WHO FC) to Week 26
Description	WHO FC is a classification which reflects disease severity based on symptoms. WHO Functional Classification of pulmonary hypertension comprises of Class I (participants with pulmonary hypertension but without resulting limitation of physical activity), II (participants with pulmonary hypertension resulting in slight limitation of physical activity), III (participants with pulmonary hypertension resulting in marked limitation of physical activity) and IV (participants with pulmonary hypertension with inability to carry out any physical activity without symptoms). Changes from baseline to Week 26 included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or unchanged/stable (same FC at baseline and at the post-baseline time point).
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

Safety Set included all screened participants who received at least one dose of study drug.

Arm/Group Title	Macitanten 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
Measure Participants	87
Missing WHO FC	5 5.7%
Worsened WHO FC	1 1.1%
Unchanged WHO FC	35 40.2%
Improved WHO FC	46 52.9%

Adverse Events

Time Frame	Up to 420 Days
Adverse Event Reporting Description	Safety Set included all screened participants who received at least one dose of study drug.
Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.
All Cause Mortality
	Macitentan 10 mg
	Affected / at Risk (%)	# Events
Total	1/87 (1.1%)
Serious Adverse Events
	Macitentan 10 mg
	Affected / at Risk (%)	# Events
Total	15/87 (17.2%)
Blood and lymphatic system disorders
Anaemia	1/87 (1.1%)
Haemolytic Anaemia	1/87 (1.1%)
Iron Deficiency Anaemia	1/87 (1.1%)
Cardiac disorders
Acute Myocardial Infarction	2/87 (2.3%)
Angina Pectoris	1/87 (1.1%)
Atrial Fibrillation	1/87 (1.1%)
Cardiac Arrest	1/87 (1.1%)
Coronary Artery Disease	1/87 (1.1%)
Right Ventricular Failure	1/87 (1.1%)
Ventricular Hypokinesia	1/87 (1.1%)
Gastrointestinal disorders
Rectal Haemorrhage	1/87 (1.1%)
General disorders
Therapeutic Response Decreased	1/87 (1.1%)
Immune system disorders
Hypersensitivity	1/87 (1.1%)
Infections and infestations
Cholangitis Infective	1/87 (1.1%)
Cytomegalovirus Infection	1/87 (1.1%)
Escherichia Bacteraemia	1/87 (1.1%)
Herpes Zoster	1/87 (1.1%)
Pneumonia	3/87 (3.4%)
Sepsis	2/87 (2.3%)
Urinary Tract Infection	1/87 (1.1%)
Metabolism and nutrition disorders
Hypoglycaemia	1/87 (1.1%)
Musculoskeletal and connective tissue disorders
Rheumatoid Arthritis	1/87 (1.1%)
Systemic Lupus Erythematosus	1/87 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic Carcinoma	1/87 (1.1%)
Nervous system disorders
Syncope	1/87 (1.1%)
Renal and urinary disorders
Acute Kidney Injury	1/87 (1.1%)
Reproductive system and breast disorders
Dysfunctional Uterine Bleeding	1/87 (1.1%)
Dysmenorrhoea	1/87 (1.1%)
Menorrhagia	1/87 (1.1%)
Pelvic Haemorrhage	1/87 (1.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/87 (1.1%)
Epistaxis	1/87 (1.1%)
Pulmonary Arterial Hypertension	2/87 (2.3%)
Pulmonary Embolism	2/87 (2.3%)
Other (Not Including Serious) Adverse Events
	Macitentan 10 mg
	Affected / at Risk (%)	# Events
Total	57/87 (65.5%)
Gastrointestinal disorders
Diarrhoea	8/87 (9.2%)
Nausea	6/87 (6.9%)
General disorders
Oedema Peripheral	19/87 (21.8%)
Pyrexia	7/87 (8%)
Infections and infestations
Nasopharyngitis	6/87 (6.9%)
Upper Respiratory Tract Infection	10/87 (11.5%)
Investigations
Haemoglobin Decreased	10/87 (11.5%)
Musculoskeletal and connective tissue disorders
Back Pain	7/87 (8%)
Myalgia	9/87 (10.3%)
Pain in Extremity	6/87 (6.9%)
Nervous system disorders
Dizziness	12/87 (13.8%)
Headache	18/87 (20.7%)
Respiratory, thoracic and mediastinal disorders
Cough	10/87 (11.5%)
Nasal Congestion	8/87 (9.2%)
Vascular disorders
Flushing	5/87 (5.7%)

Limitations/Caveats

Due to the open-label non-comparative design of study, it cannot be excluded that 6MWD and WHO FC could have been influenced by participants' knowledge that they did receive an active treatment whose efficacy had already been demonstrated.

More Information

Certain Agreements

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

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.