Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects

Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Adult and Adolescent Subjects

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03153137

Acronym

RUBATO

Enrollment

142

Registered

2017-05-15

Start date

2017-08-14

Completion date

2021-07-26

Last updated

2025-03-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Congenital Heart Disease

Brief summary

The primary objective is to assess the effect of macitentan 10 mg as compared to placebo on exercise capacity through cardiopulmonary exercise testing.

Interventions

DRUGMacitentan 10 mg

film-coated tablet; oral use

DRUGPlacebo

film-coated tablet; oral use

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

12 Years to No maximum

Healthy volunteers

Inclusion criteria

* Written informed consent/assent from the subject and/or a legal representative prior to initiation of any study-mandated procedures * Fontan-palliated subjects with either intra-atrial lateral tunnel total cavopulmonary connection (LT-TCPC), or extra cardiac tunnel TCPC (EC-TCPC) surgery \> 1 year before Screening. Either LT- or EC-TCPC can be primary or secondary to atrio-pulmonary connection * New York Heart Association (NYHA) functional class (FC) II or III (assessed by the investigator using the Specific Activity Scale * Women of childbearing potential must have a negative serum pregnancy test use reliable contraception

Exclusion criteria

* Pattern of Fontan circulation severity * Deterioration of the Fontan-palliated condition. * Limitations to Cardiopulmonary exercise testing (CPET) * Peak VO2 \< 15 mL/kg/min. * Any known factor or disease that may interfere with treatment compliance or full participation in the study

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) Up to Week 16	Baseline up to Week 16	Change from baseline in peak VO2 up to Week 16 was reported.

Secondary

Measure	Time frame	Description
Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) Up to Week 16	Baseline up to Week 16	Change from baseline in mean count per minute of daily PA-Ac up to Week 16 was reported. The daily physical activity (counts per min) of the participant was assessed via accelerometer during daytime. The accelerometer was given to the participant at Visit 1, and data was collected for 9 consecutive daily daytime periods after Visit 1 (baseline) to Visit 4 (Week 16).
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)	Up to 56 weeks	SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above.
Number of Participants With Treatment-emergent Adverse Events (AEs)	Up to 56 weeks	An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment	Up to 56 weeks	Number of participants with AEs leading to premature discontinuation of study treatment was reported. AEs leading to premature discontinuation of study treatment were those with action taken with study drug reported as 'permanently discontinued' by the investigator.
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in systolic and diastolic arterial BP at Week 8, Week 16, Week 32 and Week 52 was reported.
Change From Baseline in Pulse Rate	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in pulse rate at Week 8, Week 16, Week 32 and Week 52 was reported.
Change From Baseline in Oxygen Saturation (SpO2)	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in SpO2 was reported.
Change From Baseline in Body Weight	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in body weight was reported.
Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Up to 56 weeks	Number of participants with treatment-emergent markedly laboratory abnormal laboratory values were reported. Abnormal values for platelets (LL \< 75); Lymphocytes (HH \> 4.0); Neutrophils (LL \< 1.5); Prothrombin International Normalized Ratio: HH (greater than and equal to \[\>=\] 1.5 upper limit of normal \[ULN\]), Ratio: HH \>= 2.5 ULN); Bilirubin (HH \>= 2 ULN); Alkaline Phosphatase (HH \> 2.5 ULN); Glomerular Filtration Rate (LL \< 60); Glucose (HH \> 8.9); Triglycerides (HH \> 3.42). Here HH refers to values above the normal range, where H stands for high and LL refers to values below the normal range where L stands for low.
Change From Baseline in Hemoglobin	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in hemoglobin was reported.
Change From Baseline in Hematocrit	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in hematocrit was reported.
Change From Baseline in Erythrocytes and Reticulocytes	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in erythrocytes and reticulocytes at Week 8, Week 16, Week 32 and Week 52 was reported.
Change From Baseline in Peak VO2 Up to Week 52	Baseline up to Week 52	Change from baseline in peak VO2 up to Week 52 was reported.
Change From Baseline in Prothrombin Time	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in prothrombin time was reported.
Change From Baseline in Prothrombin International Normalized Ratio	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in prothrombin international normalized ratio was reported.
Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in ALT, AST and AP were reported.
Change From Baseline in Bilirubin and Direct Bilirubin	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in bilirubin and direct bilirubin was reported.
Change From Baseline in Gamma Glutamyl Transferase	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in gamma glutamyl transferase was reported.
Change From Baseline in Creatinine	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in creatinine was reported.
Change From Baseline in Urea Nitrogen	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in urea nitrogen was reported.
Change From Baseline in Urate	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in urate was reported.
Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in glucose, cholesterol, triglycerides, sodium, potassium, chloride and calcium was reported.
Change From Baseline in Albumin and Protein	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in albumin and protein was reported.
Change From Baseline in Alpha Fetoprotein	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in alpha fetoprotein was reported.
Change From Baseline in Cystatin C	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in cystatin C was reported.
Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Baseline, Week 8, Week 16, Week 32 and Week 52	Change from baseline in leucocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets at Week 8, Week 16, Week 32 and Week 52 was reported.

Countries

Australia, Canada, China, Czechia, Denmark, France, Germany, New Zealand, Poland, Taiwan, United Kingdom, United States

Participant flow

Pre-assignment details

A total of 142 participants were enrolled, out of which 137 participants were included in the analysis as 5 participants were excluded due to regulatory restrictions.

Participants by arm

Arm	Count
Placebo Participants received Macitentan matching placebo tablet orally, once daily with or without food starting at Week 0 up to Week 52.	69
Macitentan Participants received Macitentan 10 milligrams (mg) tablet, orally once daily with or without food starting at Week 0 up to Week 52.	68
Total	137

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	0
Overall Study	Physician Decision	0	3
Overall Study	Withdrawal by Subject	2	1

Baseline characteristics

Characteristic	Placebo	Total	Macitentan
Age, Continuous	24.5 years STANDARD_DEVIATION 7.49	23.9 years STANDARD_DEVIATION 6.72	23.2 years STANDARD_DEVIATION 5.82
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	4 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	59 Participants	117 Participants	58 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	8 Participants	16 Participants	8 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	10 Participants	16 Participants	6 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	7 Participants	14 Participants	7 Participants
Race (NIH/OMB) White	52 Participants	107 Participants	55 Participants
Region of Enrollment Australia	7 Participants	14 Participants	7 Participants
Region of Enrollment Canada	1 Participants	4 Participants	3 Participants
Region of Enrollment China	3 Participants	6 Participants	3 Participants
Region of Enrollment Czech Republic	9 Participants	20 Participants	11 Participants
Region of Enrollment Denmark	10 Participants	23 Participants	13 Participants
Region of Enrollment France	5 Participants	9 Participants	4 Participants
Region of Enrollment New Zealand	1 Participants	3 Participants	2 Participants
Region of Enrollment Poland	17 Participants	26 Participants	9 Participants
Region of Enrollment Taiwan, Province Of China	4 Participants	6 Participants	2 Participants
Region of Enrollment United Kingdom	1 Participants	4 Participants	3 Participants
Region of Enrollment United States	11 Participants	22 Participants	11 Participants
Sex: Female, Male Female	25 Participants	48 Participants	23 Participants
Sex: Female, Male Male	44 Participants	89 Participants	45 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 69	0 / 68
other Total, other adverse events	18 / 69	15 / 68
serious Total, serious adverse events	9 / 69	13 / 68

Outcome results

Primary

Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) Up to Week 16

Change from baseline in peak VO2 up to Week 16 was reported.

Time frame: Baseline up to Week 16

Population: Full analysis set (FAS) included all participants randomized to the study treatment.

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) Up to Week 16	-0.67 Milliliter/kilogram/minute (mL/kg/min)	Standard Deviation 2.657
Macitentan	Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) Up to Week 16	-0.16 Milliliter/kilogram/minute (mL/kg/min)	Standard Deviation 2.855

Comparison: Due to adaptive nature of the design, the main analysis was conducted on FAS using the inverse normal combination method with pre-specified weights to combine first and second stage p-values.p-value: =0.19399% CI: [-0.62, 1.85]ANCOVA

Secondary

Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)

Change from baseline in ALT, AST and AP were reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	ALT: Week 52	-0.2 Units per liter (U/L)	Standard Deviation 8.11
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AST: Week 32	0.9 Units per liter (U/L)	Standard Deviation 4.14
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	ALT: Week 8	-0.8 Units per liter (U/L)	Standard Deviation 5.57
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AST: Week 52	-0.6 Units per liter (U/L)	Standard Deviation 6.83
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AST: Baseline	25.8 Units per liter (U/L)	Standard Deviation 7.4
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AP: Baseline	106.4 Units per liter (U/L)	Standard Deviation 83.54
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	ALT: Week 32	-0.4 Units per liter (U/L)	Standard Deviation 5.62
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AP: Week 8	-7.6 Units per liter (U/L)	Standard Deviation 19.82
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AST: Week 8	-0.7 Units per liter (U/L)	Standard Deviation 4.92
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AP: Week 16	-4.7 Units per liter (U/L)	Standard Deviation 19.2
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	ALT: Week 16	-0.2 Units per liter (U/L)	Standard Deviation 6.86
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AP: Week 32	-10.1 Units per liter (U/L)	Standard Deviation 32.43
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AST: Week 16	-0.5 Units per liter (U/L)	Standard Deviation 6.13
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AP: Week 52	-12.9 Units per liter (U/L)	Standard Deviation 34.81
Placebo	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	ALT: Baseline	26.7 Units per liter (U/L)	Standard Deviation 9.47
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AP: Week 52	-7.0 Units per liter (U/L)	Standard Deviation 27.63
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	ALT: Baseline	28.5 Units per liter (U/L)	Standard Deviation 12.84
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	ALT: Week 8	-1.8 Units per liter (U/L)	Standard Deviation 9.99
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	ALT: Week 16	-1.6 Units per liter (U/L)	Standard Deviation 7.94
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	ALT: Week 32	-2.1 Units per liter (U/L)	Standard Deviation 12.53
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	ALT: Week 52	-0.3 Units per liter (U/L)	Standard Deviation 14.04
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AST: Baseline	28.3 Units per liter (U/L)	Standard Deviation 20.95
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AST: Week 8	-4.4 Units per liter (U/L)	Standard Deviation 2.37
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AST: Week 16	-3.9 Units per liter (U/L)	Standard Deviation 20.25
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AST: Week 32	-4.7 Units per liter (U/L)	Standard Deviation 22.46
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AST: Week 52	-3.2 Units per liter (U/L)	Standard Deviation 24.16
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AP: Baseline	100.2 Units per liter (U/L)	Standard Deviation 88.62
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AP: Week 8	-8.5 Units per liter (U/L)	Standard Deviation 18.14
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AP: Week 16	-7.1 Units per liter (U/L)	Standard Deviation 22.54
Macitentan	Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	AP: Week 32	-1.1 Units per liter (U/L)	Standard Deviation 26.3

Secondary

Change From Baseline in Albumin and Protein

Change from baseline in albumin and protein was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Albumin and Protein	Albumin: Baseline	48.64 grams per liter (g/L)	Standard Deviation 3.024
Placebo	Change From Baseline in Albumin and Protein	Albumin: Week 8	-0.74 grams per liter (g/L)	Standard Deviation 2.789
Placebo	Change From Baseline in Albumin and Protein	Albumin: Week 16	0.61 grams per liter (g/L)	Standard Deviation 2.821
Placebo	Change From Baseline in Albumin and Protein	Albumin: Week 32	0.79 grams per liter (g/L)	Standard Deviation 3.276
Placebo	Change From Baseline in Albumin and Protein	Albumin: Week 52	-0.08 grams per liter (g/L)	Standard Deviation 3.426
Placebo	Change From Baseline in Albumin and Protein	Protein: Baseline	75.0 grams per liter (g/L)	Standard Deviation 4.73
Placebo	Change From Baseline in Albumin and Protein	Protein: Week 8	-1.5 grams per liter (g/L)	Standard Deviation 4.28
Placebo	Change From Baseline in Albumin and Protein	Protein: Week 16	-0.3 grams per liter (g/L)	Standard Deviation 4.62
Placebo	Change From Baseline in Albumin and Protein	Protein: Week 32	-0.2 grams per liter (g/L)	Standard Deviation 4.38
Placebo	Change From Baseline in Albumin and Protein	Protein: Week 52	-1.8 grams per liter (g/L)	Standard Deviation 5.42
Macitentan	Change From Baseline in Albumin and Protein	Protein: Week 16	-1.9 grams per liter (g/L)	Standard Deviation 4.51
Macitentan	Change From Baseline in Albumin and Protein	Albumin: Baseline	49.56 grams per liter (g/L)	Standard Deviation 3.257
Macitentan	Change From Baseline in Albumin and Protein	Protein: Baseline	75.4 grams per liter (g/L)	Standard Deviation 5.24
Macitentan	Change From Baseline in Albumin and Protein	Albumin: Week 8	-1.73 grams per liter (g/L)	Standard Deviation 2.922
Macitentan	Change From Baseline in Albumin and Protein	Protein: Week 52	-2.5 grams per liter (g/L)	Standard Deviation 5.56
Macitentan	Change From Baseline in Albumin and Protein	Albumin: Week 16	-0.82 grams per liter (g/L)	Standard Deviation 3.274
Macitentan	Change From Baseline in Albumin and Protein	Protein: Week 8	-3.8 grams per liter (g/L)	Standard Deviation 4.38
Macitentan	Change From Baseline in Albumin and Protein	Albumin: Week 32	0.38 grams per liter (g/L)	Standard Deviation 3.462
Macitentan	Change From Baseline in Albumin and Protein	Protein: Week 32	-0.3 grams per liter (g/L)	Standard Deviation 4.6
Macitentan	Change From Baseline in Albumin and Protein	Albumin: Week 52	-0.53 grams per liter (g/L)	Standard Deviation 3.339

Secondary

Change From Baseline in Alpha Fetoprotein

Change from baseline in alpha fetoprotein was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Alpha Fetoprotein	Week 8	0.006 micrograms per milliliter (ug/L)	Standard Deviation 0.5537
Placebo	Change From Baseline in Alpha Fetoprotein	Week 32	0.033 micrograms per milliliter (ug/L)	Standard Deviation 0.3911
Placebo	Change From Baseline in Alpha Fetoprotein	Week 16	0.055 micrograms per milliliter (ug/L)	Standard Deviation 0.4373
Placebo	Change From Baseline in Alpha Fetoprotein	Week 52	0.068 micrograms per milliliter (ug/L)	Standard Deviation 0.5003
Placebo	Change From Baseline in Alpha Fetoprotein	Baseline	3.145 micrograms per milliliter (ug/L)	Standard Deviation 2.0135
Macitentan	Change From Baseline in Alpha Fetoprotein	Week 52	0.240 micrograms per milliliter (ug/L)	Standard Deviation 0.6349
Macitentan	Change From Baseline in Alpha Fetoprotein	Baseline	3.326 micrograms per milliliter (ug/L)	Standard Deviation 2.2213
Macitentan	Change From Baseline in Alpha Fetoprotein	Week 8	-0.061 micrograms per milliliter (ug/L)	Standard Deviation 0.6314
Macitentan	Change From Baseline in Alpha Fetoprotein	Week 16	0.160 micrograms per milliliter (ug/L)	Standard Deviation 0.5667
Macitentan	Change From Baseline in Alpha Fetoprotein	Week 32	0.191 micrograms per milliliter (ug/L)	Standard Deviation 0.5959

Secondary

Change From Baseline in Bilirubin and Direct Bilirubin

Change from baseline in bilirubin and direct bilirubin was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Bilirubin and Direct Bilirubin	Bilirubin: Baseline	14.65 micromole per liter (umol/L)	Standard Deviation 5.815
Placebo	Change From Baseline in Bilirubin and Direct Bilirubin	Bilirubin: Week 8	0.62 micromole per liter (umol/L)	Standard Deviation 5.985
Placebo	Change From Baseline in Bilirubin and Direct Bilirubin	Bilirubin: Week 16	1.98 micromole per liter (umol/L)	Standard Deviation 5.799
Placebo	Change From Baseline in Bilirubin and Direct Bilirubin	Bilirubin: Week 32	1.47 micromole per liter (umol/L)	Standard Deviation 5.285
Placebo	Change From Baseline in Bilirubin and Direct Bilirubin	Bilirubin: Week 52	0.69 micromole per liter (umol/L)	Standard Deviation 5.778
Placebo	Change From Baseline in Bilirubin and Direct Bilirubin	Direct Bilirubin: Baseline	4.04 micromole per liter (umol/L)	Standard Deviation 1.397
Placebo	Change From Baseline in Bilirubin and Direct Bilirubin	Direct Bilirubin: Week 8	-0.06 micromole per liter (umol/L)	Standard Deviation 1.105
Placebo	Change From Baseline in Bilirubin and Direct Bilirubin	Direct Bilirubin: Week 16	0.24 micromole per liter (umol/L)	Standard Deviation 1.088
Placebo	Change From Baseline in Bilirubin and Direct Bilirubin	Direct Bilirubin: Week 32	0.00 micromole per liter (umol/L)	Standard Deviation 1.029
Placebo	Change From Baseline in Bilirubin and Direct Bilirubin	Direct Bilirubin: Week 52	0.28 micromole per liter (umol/L)	Standard Deviation 1.28
Macitentan	Change From Baseline in Bilirubin and Direct Bilirubin	Direct Bilirubin: Week 16	-0.28 micromole per liter (umol/L)	Standard Deviation 1.227
Macitentan	Change From Baseline in Bilirubin and Direct Bilirubin	Bilirubin: Baseline	17.28 micromole per liter (umol/L)	Standard Deviation 13.379
Macitentan	Change From Baseline in Bilirubin and Direct Bilirubin	Direct Bilirubin: Baseline	4.38 micromole per liter (umol/L)	Standard Deviation 1.719
Macitentan	Change From Baseline in Bilirubin and Direct Bilirubin	Bilirubin: Week 8	-1.08 micromole per liter (umol/L)	Standard Deviation 5.693
Macitentan	Change From Baseline in Bilirubin and Direct Bilirubin	Direct Bilirubin: Week 52	-0.24 micromole per liter (umol/L)	Standard Deviation 1.228
Macitentan	Change From Baseline in Bilirubin and Direct Bilirubin	Bilirubin: Week 16	-1.76 micromole per liter (umol/L)	Standard Deviation 7.075
Macitentan	Change From Baseline in Bilirubin and Direct Bilirubin	Direct Bilirubin: Week 8	-0.22 micromole per liter (umol/L)	Standard Deviation 1.149
Macitentan	Change From Baseline in Bilirubin and Direct Bilirubin	Bilirubin: Week 32	0.29 micromole per liter (umol/L)	Standard Deviation 5.052
Macitentan	Change From Baseline in Bilirubin and Direct Bilirubin	Direct Bilirubin: Week 32	-0.04 micromole per liter (umol/L)	Standard Deviation 1.147
Macitentan	Change From Baseline in Bilirubin and Direct Bilirubin	Bilirubin: Week 52	-1.02 micromole per liter (umol/L)	Standard Deviation 5.778

Secondary

Change From Baseline in Body Weight

Change from baseline in body weight was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Body Weight	Week 8	-0.38 kilograms (kg)	Standard Deviation 1.996
Placebo	Change From Baseline in Body Weight	Week 32	0.73 kilograms (kg)	Standard Deviation 2.952
Placebo	Change From Baseline in Body Weight	Week 16	0.21 kilograms (kg)	Standard Deviation 2.028
Placebo	Change From Baseline in Body Weight	Week 52	1.44 kilograms (kg)	Standard Deviation 3.746
Placebo	Change From Baseline in Body Weight	Baseline	68.89 kilograms (kg)	Standard Deviation 17.296
Macitentan	Change From Baseline in Body Weight	Week 52	1.30 kilograms (kg)	Standard Deviation 4.358
Macitentan	Change From Baseline in Body Weight	Baseline	67.38 kilograms (kg)	Standard Deviation 14.721
Macitentan	Change From Baseline in Body Weight	Week 8	0.43 kilograms (kg)	Standard Deviation 1.568
Macitentan	Change From Baseline in Body Weight	Week 16	0.58 kilograms (kg)	Standard Deviation 2.23
Macitentan	Change From Baseline in Body Weight	Week 32	0.77 kilograms (kg)	Standard Deviation 3.411

Secondary

Change From Baseline in Creatinine

Change from baseline in creatinine was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here, N (number of participants analyzed) signifies participants evaluable for this outcome measure. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Creatinine	Week 8	-2.0 micromole/liter (umol/L)	Standard Deviation 7.49
Placebo	Change From Baseline in Creatinine	Week 32	2.2 micromole/liter (umol/L)	Standard Deviation 10.81
Placebo	Change From Baseline in Creatinine	Baseline	78.1 micromole/liter (umol/L)	Standard Deviation 14.36
Placebo	Change From Baseline in Creatinine	Week 52	-1.5 micromole/liter (umol/L)	Standard Deviation 9.52
Placebo	Change From Baseline in Creatinine	Week 16	-1.1 micromole/liter (umol/L)	Standard Deviation 10.72
Macitentan	Change From Baseline in Creatinine	Week 52	0.4 micromole/liter (umol/L)	Standard Deviation 10
Macitentan	Change From Baseline in Creatinine	Week 8	-6.2 micromole/liter (umol/L)	Standard Deviation 7.49
Macitentan	Change From Baseline in Creatinine	Week 16	-0.3 micromole/liter (umol/L)	Standard Deviation 12.46
Macitentan	Change From Baseline in Creatinine	Week 32	-1.8 micromole/liter (umol/L)	Standard Deviation 13.46
Macitentan	Change From Baseline in Creatinine	Baseline	78.9 micromole/liter (umol/L)	Standard Deviation 17.42

Secondary

Change From Baseline in Cystatin C

Change from baseline in cystatin C was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Cystatin C	Week 8	-0.026 milligrams per liter (mg/L)	Standard Deviation 0.0563
Placebo	Change From Baseline in Cystatin C	Week 32	-0.038 milligrams per liter (mg/L)	Standard Deviation 0.0659
Placebo	Change From Baseline in Cystatin C	Week 16	-0.017 milligrams per liter (mg/L)	Standard Deviation 0.1464
Placebo	Change From Baseline in Cystatin C	Week 52	-0.001 milligrams per liter (mg/L)	Standard Deviation 0.0723
Placebo	Change From Baseline in Cystatin C	Baseline	0.742 milligrams per liter (mg/L)	Standard Deviation 0.1047
Macitentan	Change From Baseline in Cystatin C	Week 52	0.010 milligrams per liter (mg/L)	Standard Deviation 0.0927
Macitentan	Change From Baseline in Cystatin C	Baseline	0.718 milligrams per liter (mg/L)	Standard Deviation 0.119
Macitentan	Change From Baseline in Cystatin C	Week 8	-0.019 milligrams per liter (mg/L)	Standard Deviation 0.0782
Macitentan	Change From Baseline in Cystatin C	Week 16	-0.019 milligrams per liter (mg/L)	Standard Deviation 0.0964
Macitentan	Change From Baseline in Cystatin C	Week 32	-0.021 milligrams per liter (mg/L)	Standard Deviation 0.0701

Secondary

Change From Baseline in Erythrocytes and Reticulocytes

Change from baseline in erythrocytes and reticulocytes at Week 8, Week 16, Week 32 and Week 52 was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Erythrocytes and Reticulocytes	Erythrocytes: Week 8	0.048 10^12 cells per liter	Standard Deviation 0.2461
Placebo	Change From Baseline in Erythrocytes and Reticulocytes	Reticulocytes: Baseline:	0.075 10^12 cells per liter	Standard Deviation 0.028
Placebo	Change From Baseline in Erythrocytes and Reticulocytes	Erythrocytes: Week 32	-0.031 10^12 cells per liter	Standard Deviation 0.2442
Placebo	Change From Baseline in Erythrocytes and Reticulocytes	Reticulocytes: Week 8	-0.006 10^12 cells per liter	Standard Deviation 0.017
Placebo	Change From Baseline in Erythrocytes and Reticulocytes	Erythrocytes: Week 16	0.012 10^12 cells per liter	Standard Deviation 0.2521
Placebo	Change From Baseline in Erythrocytes and Reticulocytes	Reticulocytes: Week 16	-0.003 10^12 cells per liter	Standard Deviation 0.026
Placebo	Change From Baseline in Erythrocytes and Reticulocytes	Erythrocytes: Week 52	-0.096 10^12 cells per liter	Standard Deviation 0.2515
Placebo	Change From Baseline in Erythrocytes and Reticulocytes	Reticulocytes: Week 32	-0.003 10^12 cells per liter	Standard Deviation 0.028
Placebo	Change From Baseline in Erythrocytes and Reticulocytes	Erythrocytes: Baseline	5.251 10^12 cells per liter	Standard Deviation 0.4832
Macitentan	Change From Baseline in Erythrocytes and Reticulocytes	Reticulocytes: Week 32	-0.008 10^12 cells per liter	Standard Deviation 0.027
Macitentan	Change From Baseline in Erythrocytes and Reticulocytes	Erythrocytes: Baseline	5.205 10^12 cells per liter	Standard Deviation 0.3544
Macitentan	Change From Baseline in Erythrocytes and Reticulocytes	Erythrocytes: Week 8	-0.297 10^12 cells per liter	Standard Deviation 0.2866
Macitentan	Change From Baseline in Erythrocytes and Reticulocytes	Erythrocytes: Week 16	-0.264 10^12 cells per liter	Standard Deviation 0.279
Macitentan	Change From Baseline in Erythrocytes and Reticulocytes	Erythrocytes: Week 32	-0.090 10^12 cells per liter	Standard Deviation 0.2337
Macitentan	Change From Baseline in Erythrocytes and Reticulocytes	Erythrocytes: Week 52	-0.184 10^12 cells per liter	Standard Deviation 0.2671
Macitentan	Change From Baseline in Erythrocytes and Reticulocytes	Reticulocytes: Baseline:	0.070 10^12 cells per liter	Standard Deviation 0.022
Macitentan	Change From Baseline in Erythrocytes and Reticulocytes	Reticulocytes: Week 8	-0.006 10^12 cells per liter	Standard Deviation 0.016
Macitentan	Change From Baseline in Erythrocytes and Reticulocytes	Reticulocytes: Week 16	-0.001 10^12 cells per liter	Standard Deviation 0.021

Secondary

Change From Baseline in Gamma Glutamyl Transferase

Change from baseline in gamma glutamyl transferase was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Gamma Glutamyl Transferase	Week 32	-1.3 Units per liter (U/L)	Standard Deviation 13.39
Placebo	Change From Baseline in Gamma Glutamyl Transferase	Week 52	-3.2 Units per liter (U/L)	Standard Deviation 22.4
Placebo	Change From Baseline in Gamma Glutamyl Transferase	Baseline	67.6 Units per liter (U/L)	Standard Deviation 43.02
Placebo	Change From Baseline in Gamma Glutamyl Transferase	Week 8	-4.8 Units per liter (U/L)	Standard Deviation 13.22
Placebo	Change From Baseline in Gamma Glutamyl Transferase	Week 16	-4.4 Units per liter (U/L)	Standard Deviation 13.79
Macitentan	Change From Baseline in Gamma Glutamyl Transferase	Week 16	0.7 Units per liter (U/L)	Standard Deviation 27.43
Macitentan	Change From Baseline in Gamma Glutamyl Transferase	Week 8	-5.5 Units per liter (U/L)	Standard Deviation 12.56
Macitentan	Change From Baseline in Gamma Glutamyl Transferase	Week 52	-6.7 Units per liter (U/L)	Standard Deviation 21.31
Macitentan	Change From Baseline in Gamma Glutamyl Transferase	Week 32	-5.3 Units per liter (U/L)	Standard Deviation 23.29
Macitentan	Change From Baseline in Gamma Glutamyl Transferase	Baseline	79.4 Units per liter (U/L)	Standard Deviation 45.89

Secondary

Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium

Change from baseline in glucose, cholesterol, triglycerides, sodium, potassium, chloride and calcium was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Glucose: Week 16	0.17 mmol/L	Standard Deviation 1.153
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Sodium: Week 8	-0.5 mmol/L	Standard Deviation 2.02
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Cholesterol: Week 16	-0.065 mmol/L	Standard Deviation 0.3994
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Sodium: Week 16	-1.1 mmol/L	Standard Deviation 2.74
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Glucose: Baseline	4.97 mmol/L	Standard Deviation 0.772
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Sodium: Week 32	-0.7 mmol/L	Standard Deviation 3.23
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Cholesterol: Week 32	0.060 mmol/L	Standard Deviation 0.5185
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Sodium: Week 52	-1.1 mmol/L	Standard Deviation 2.28
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Glucose: Week 32	0.24 mmol/L	Standard Deviation 0.911
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Potassium: Baseline	4.364 mmol/L	Standard Deviation 0.2695
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Cholesterol: Week 52	-0.065 mmol/L	Standard Deviation 0.4308
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Potassium: Week 8	-0.074 mmol/L	Standard Deviation 0.3476
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Calcium: Week 32	0.035 mmol/L	Standard Deviation 0.0987
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Potassium: Week 16	-0.013 mmol/L	Standard Deviation 0.3684
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Triglycerides: Baseline	1.126 mmol/L	Standard Deviation 0.4787
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Potassium: Week 32	-0.011 mmol/L	Standard Deviation 0.3957
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Glucose: Week 52	-0.03 mmol/L	Standard Deviation 0.883
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Potassium: Week 52	-0.031 mmol/L	Standard Deviation 0.3354
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Triglycerides: Week 8	-0.061 mmol/L	Standard Deviation 0.595
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Chloride: Baseline	103.9 mmol/L	Standard Deviation 2.19
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Glucose: Week 8	0.00 mmol/L	Standard Deviation 1.028
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Chloride: Week 8	0.2 mmol/L	Standard Deviation 1.71
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Triglycerides: Week 16	-0.099 mmol/L	Standard Deviation 0.3946
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Chloride: Week 16	-0.4 mmol/L	Standard Deviation 2.88
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Cholesterol: Baseline	3.653 mmol/L	Standard Deviation 0.7454
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Chloride: Week 32	-0.1 mmol/L	Standard Deviation 2.37
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Triglycerides: Week 32	0.123 mmol/L	Standard Deviation 0.4749
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Chloride: Week 52	0.4 mmol/L	Standard Deviation 2.44
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Calcium: Week 52	-0.021 mmol/L	Standard Deviation 0.1083
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Calcium: Baseline	2.458 mmol/L	Standard Deviation 0.099
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Triglycerides: Week 52	-0.067 mmol/L	Standard Deviation 0.5191
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Calcium: Week 8	-0.006 mmol/L	Standard Deviation 0.1096
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Cholesterol: Week 8	-0.182 mmol/L	Standard Deviation 0.3808
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Calcium: Week 16	-0.002 mmol/L	Standard Deviation 0.0929
Placebo	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Sodium: Baseline	141.2 mmol/L	Standard Deviation 1.93
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Calcium: Week 52	-0.035 mmol/L	Standard Deviation 0.1093
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Calcium: Week 32	-0.004 mmol/L	Standard Deviation 0.1271
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Glucose: Baseline	5.15 mmol/L	Standard Deviation 0.868
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Glucose: Week 8	-0.46 mmol/L	Standard Deviation 0.914
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Glucose: Week 16	-0.04 mmol/L	Standard Deviation 1.022
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Glucose: Week 32	-0.12 mmol/L	Standard Deviation 0.85
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Glucose: Week 52	-0.28 mmol/L	Standard Deviation 1.193
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Cholesterol: Baseline	3.705 mmol/L	Standard Deviation 0.6676
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Cholesterol: Week 8	-0.238 mmol/L	Standard Deviation 0.3807
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Cholesterol: Week 16	-0.190 mmol/L	Standard Deviation 0.5139
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Cholesterol: Week 32	-0.059 mmol/L	Standard Deviation 0.5364
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Cholesterol: Week 52	-0.093 mmol/L	Standard Deviation 0.4243
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Triglycerides: Baseline	1.057 mmol/L	Standard Deviation 0.4233
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Triglycerides: Week 8	-0.071 mmol/L	Standard Deviation 0.3755
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Triglycerides: Week 16	-0.004 mmol/L	Standard Deviation 0.4244
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Triglycerides: Week 32	0.024 mmol/L	Standard Deviation 0.5126
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Triglycerides: Week 52	-0.020 mmol/L	Standard Deviation 0.4703
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Sodium: Baseline	140.8 mmol/L	Standard Deviation 2.79
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Sodium: Week 8	-0.2 mmol/L	Standard Deviation 2.52
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Sodium: Week 16	-0.6 mmol/L	Standard Deviation 2.94
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Sodium: Week 32	-0.3 mmol/L	Standard Deviation 2.44
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Sodium: Week 52	-1.0 mmol/L	Standard Deviation 2.35
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Potassium: Baseline	4.391 mmol/L	Standard Deviation 0.2885
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Potassium: Week 8	-0.030 mmol/L	Standard Deviation 0.2876
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Potassium: Week 16	0.030 mmol/L	Standard Deviation 0.3783
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Potassium: Week 32	-0.033 mmol/L	Standard Deviation 0.2599
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Potassium: Week 52	-0.003 mmol/L	Standard Deviation 0.3356
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Chloride: Baseline	103.3 mmol/L	Standard Deviation 3.3
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Chloride: Week 8	1.3 mmol/L	Standard Deviation 2.33
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Chloride: Week 16	0.3 mmol/L	Standard Deviation 2.75
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Chloride: Week 32	0.3 mmol/L	Standard Deviation 2.28
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Chloride: Week 52	0.4 mmol/L	Standard Deviation 2.89
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Calcium: Baseline	2.479 mmol/L	Standard Deviation 0.1114
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Calcium: Week 8	-0.062 mmol/L	Standard Deviation 0.0999
Macitentan	Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Calcium: Week 16	-0.050 mmol/L	Standard Deviation 0.0943

Secondary

Change From Baseline in Hematocrit

Change from baseline in hematocrit was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Hematocrit	Week 52	-0.010 Liter/Liter (L/L)	Standard Deviation 0.03
Placebo	Change From Baseline in Hematocrit	Week 16	0.003 Liter/Liter (L/L)	Standard Deviation 0.027
Placebo	Change From Baseline in Hematocrit	Week 8	0.002 Liter/Liter (L/L)	Standard Deviation 0.027
Placebo	Change From Baseline in Hematocrit	Week 32	0.003 Liter/Liter (L/L)	Standard Deviation 0.031
Placebo	Change From Baseline in Hematocrit	Baseline	0.472 Liter/Liter (L/L)	Standard Deviation 0.041
Macitentan	Change From Baseline in Hematocrit	Week 32	-0.009 Liter/Liter (L/L)	Standard Deviation 0.028
Macitentan	Change From Baseline in Hematocrit	Week 52	-0.021 Liter/Liter (L/L)	Standard Deviation 0.028
Macitentan	Change From Baseline in Hematocrit	Baseline	0.471 Liter/Liter (L/L)	Standard Deviation 0.034
Macitentan	Change From Baseline in Hematocrit	Week 8	-0.030 Liter/Liter (L/L)	Standard Deviation 0.023
Macitentan	Change From Baseline in Hematocrit	Week 16	-0.023 Liter/Liter (L/L)	Standard Deviation 0.026

Secondary

Change From Baseline in Hemoglobin

Change from baseline in hemoglobin was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here, N (number of participants analyzed) signifies number of participants evaluable for this outcome measure. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Hemoglobin	Week 8	0.0 grams per liter (g/L)	Standard Deviation 6.59
Placebo	Change From Baseline in Hemoglobin	Week 16	0.0 grams per liter (g/L)	Standard Deviation 7.75
Placebo	Change From Baseline in Hemoglobin	Week 32	1.3 grams per liter (g/L)	Standard Deviation 8.29
Placebo	Change From Baseline in Hemoglobin	Week 52	-2.9 grams per liter (g/L)	Standard Deviation 10.04
Placebo	Change From Baseline in Hemoglobin	Baseline	160.4 grams per liter (g/L)	Standard Deviation 13.43
Macitentan	Change From Baseline in Hemoglobin	Baseline	159.5 grams per liter (g/L)	Standard Deviation 12.83
Macitentan	Change From Baseline in Hemoglobin	Week 52	-7.1 grams per liter (g/L)	Standard Deviation 10.02
Macitentan	Change From Baseline in Hemoglobin	Week 16	-8.7 grams per liter (g/L)	Standard Deviation 8.51
Macitentan	Change From Baseline in Hemoglobin	Week 8	-8.7 grams per liter (g/L)	Standard Deviation 9.33
Macitentan	Change From Baseline in Hemoglobin	Week 32	-7.3 grams per liter (g/L)	Standard Deviation 9.84

Secondary

Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets

Change from baseline in leucocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets at Week 8, Week 16, Week 32 and Week 52 was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Monocytes: Week 8	-0.017 10^9 cells per liter	Standard Deviation 0.1645
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Leukocytes: Week 32	0.417 10^9 cells per liter	Standard Deviation 1.1782
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Monocytes: Week 16	0.002 10^9 cells per liter	Standard Deviation 0.1703
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Neutrophils: Week 32	0.494 10^9 cells per liter	Standard Deviation 0.9719
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Monocytes: Week 32	-0.018 10^9 cells per liter	Standard Deviation 0.1209
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Leukocytes: Week 8	-0.242 10^9 cells per liter	Standard Deviation 1.7651
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Monocytes: Week 52	-0.039 10^9 cells per liter	Standard Deviation 0.138
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Neutrophils: Week 52	-0.384 10^9 cells per liter	Standard Deviation 1.1619
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Eosinophils: Baseline	0.207 10^9 cells per liter	Standard Deviation 0.348
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Leukocytes: Week 52	-0.554 10^9 cells per liter	Standard Deviation 1.405
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Eosinophils: Week 8	-0.003 10^9 cells per liter	Standard Deviation 0.5146
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Lymphocytes: Baseline	1.489 10^9 cells per liter	Standard Deviation 0.6791
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Eosinophils: Week 16	0.016 10^9 cells per liter	Standard Deviation 0.3056
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Leukocytes: Baseline	6.270 10^9 cells per liter	Standard Deviation 1.7553
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Eosinophils: Week 32	-0.100 10^9 cells per liter	Standard Deviation 0.5447
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Lymphocytes: Week 8	-0.113 10^9 cells per liter	Standard Deviation 0.477
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Eosinophils: Week 52	-0.046 10^9 cells per liter	Standard Deviation 0.3597
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Neutrophils: Baseline	4.100 10^9 cells per liter	Standard Deviation 1.3222
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Basophils: Baseline	0.055 10^9 cells per liter	Standard Deviation 0.0322
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Lymphocytes: Week 16	0.073 10^9 cells per liter	Standard Deviation 0.4756
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Basophils: Week 16	0.004 10^9 cells per liter	Standard Deviation 0.0394
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Leukocytes: Week 16	-0.199 10^9 cells per liter	Standard Deviation 1.549
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Basophils: Week 32	-0.003 10^9 cells per liter	Standard Deviation 0.0354
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Lymphocytes: Week 32	0.047 10^9 cells per liter	Standard Deviation 0.3341
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Basophils: Week 52	-0.003 10^9 cells per liter	Standard Deviation 0.0389
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Platelets: Baseline	184.3 10^9 cells per liter	Standard Deviation 63.22
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Neutrophils: Week 8	-0.133 10^9 cells per liter	Standard Deviation 1.3604
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Platelets: Week 8	-5.9 10^9 cells per liter	Standard Deviation 32.85
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Lymphocytes: Week 52	-0.082 10^9 cells per liter	Standard Deviation 0.474
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Platelets: Week 16	-5.4 10^9 cells per liter	Standard Deviation 30.33
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Basophils: Week 8	-0.002 10^9 cells per liter	Standard Deviation 0.0255
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Platelets: Week 32	-7.8 10^9 cells per liter	Standard Deviation 33.46
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Baseline: Monocytes	0.416 10^9 cells per liter	Standard Deviation 0.1698
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Platelets: Week 52	-11.2 10^9 cells per liter	Standard Deviation 29.94
Placebo	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Neutrophils: Week 16	-0.291 10^9 cells per liter	Standard Deviation 1.3547
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Platelets: Week 52	-5.7 10^9 cells per liter	Standard Deviation 31.75
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Basophils: Week 52	0.006 10^9 cells per liter	Standard Deviation 0.0281
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Leukocytes: Baseline	5.693 10^9 cells per liter	Standard Deviation 1.5679
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Leukocytes: Week 8	-1.001 10^9 cells per liter	Standard Deviation 1.2096
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Leukocytes: Week 16	-0.378 10^9 cells per liter	Standard Deviation 1.3908
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Leukocytes: Week 32	-0.237 10^9 cells per liter	Standard Deviation 1.7224
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Leukocytes: Week 52	-0.715 10^9 cells per liter	Standard Deviation 1.6433
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Neutrophils: Baseline	3.831 10^9 cells per liter	Standard Deviation 1.1268
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Neutrophils: Week 8	-0.743 10^9 cells per liter	Standard Deviation 0.9864
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Neutrophils: Week 16	-0.373 10^9 cells per liter	Standard Deviation 1.0896
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Neutrophils: Week 32	-0.254 10^9 cells per liter	Standard Deviation 1.2012
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Neutrophils: Week 52	-0.627 10^9 cells per liter	Standard Deviation 1.2475
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Lymphocytes: Baseline	1.263 10^9 cells per liter	Standard Deviation 0.4974
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Lymphocytes: Week 8	-0.165 10^9 cells per liter	Standard Deviation 0.2886
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Lymphocytes: Week 16	0.042 10^9 cells per liter	Standard Deviation 0.6164
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Lymphocytes: Week 32	0.126 10^9 cells per liter	Standard Deviation 0.2269
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Lymphocytes: Week 52	-0.033 10^9 cells per liter	Standard Deviation 0.389
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Baseline: Monocytes	0.409 10^9 cells per liter	Standard Deviation 0.1541
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Monocytes: Week 8	-0.081 10^9 cells per liter	Standard Deviation 0.14
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Monocytes: Week 16	-0.050 10^9 cells per liter	Standard Deviation 0.1202
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Monocytes: Week 32	-0.071 10^9 cells per liter	Standard Deviation 0.1162
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Monocytes: Week 52	-0.077 10^9 cells per liter	Standard Deviation 0.1257
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Eosinophils: Baseline	0.151 10^9 cells per liter	Standard Deviation 0.1333
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Eosinophils: Week 8	0.014 10^9 cells per liter	Standard Deviation 0.0816
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Eosinophils: Week 16	0.002 10^9 cells per liter	Standard Deviation 0.0755
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Eosinophils: Week 32	0.029 10^9 cells per liter	Standard Deviation 0.1951
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Eosinophils: Week 52	0.015 10^9 cells per liter	Standard Deviation 0.1935
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Basophils: Week 8	-0.002 10^9 cells per liter	Standard Deviation 0.0233
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Basophils: Week 16	0.000 10^9 cells per liter	Standard Deviation 0.0363
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Basophils: Week 32	0.016 10^9 cells per liter	Standard Deviation 0.0313
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Platelets: Baseline	178.1 10^9 cells per liter	Standard Deviation 54.93
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Platelets: Week 8	-9.1 10^9 cells per liter	Standard Deviation 35.38
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Platelets: Week 16	-3.0 10^9 cells per liter	Standard Deviation 28.77
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Platelets: Week 32	8.2 10^9 cells per liter	Standard Deviation 33.76
Macitentan	Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Basophils: Baseline	0.040 10^9 cells per liter	Standard Deviation 0.0245

Secondary

Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) Up to Week 16

Change from baseline in mean count per minute of daily PA-Ac up to Week 16 was reported. The daily physical activity (counts per min) of the participant was assessed via accelerometer during daytime. The accelerometer was given to the participant at Visit 1, and data was collected for 9 consecutive daily daytime periods after Visit 1 (baseline) to Visit 4 (Week 16).

Time frame: Baseline up to Week 16

Population: FAS included all participants randomized to the study treatment. Here, N (number of participants analyzed) is defined as the number of participants evaluable for this outcome measure.

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) Up to Week 16	-14.34 counts per minute	Standard Deviation 117.562
Macitentan	Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) Up to Week 16	-3.02 counts per minute	Standard Deviation 92.443

Secondary

Change From Baseline in Oxygen Saturation (SpO2)

Change from baseline in SpO2 was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Oxygen Saturation (SpO2)	Week 8	0.0 percent of oxygen saturation	Standard Deviation 3.2
Placebo	Change From Baseline in Oxygen Saturation (SpO2)	Week 16	0.5 percent of oxygen saturation	Standard Deviation 2.57
Placebo	Change From Baseline in Oxygen Saturation (SpO2)	Week 52	1.4 percent of oxygen saturation	Standard Deviation 2.77
Placebo	Change From Baseline in Oxygen Saturation (SpO2)	Baseline	92.6 percent of oxygen saturation	Standard Deviation 3.22
Placebo	Change From Baseline in Oxygen Saturation (SpO2)	Week 32	0.8 percent of oxygen saturation	Standard Deviation 2.94
Macitentan	Change From Baseline in Oxygen Saturation (SpO2)	Week 32	1.4 percent of oxygen saturation	Standard Deviation 3.73
Macitentan	Change From Baseline in Oxygen Saturation (SpO2)	Week 8	1.2 percent of oxygen saturation	Standard Deviation 2.78
Macitentan	Change From Baseline in Oxygen Saturation (SpO2)	Baseline	92.8 percent of oxygen saturation	Standard Deviation 2.84
Macitentan	Change From Baseline in Oxygen Saturation (SpO2)	Week 16	0.8 percent of oxygen saturation	Standard Deviation 2.75
Macitentan	Change From Baseline in Oxygen Saturation (SpO2)	Week 52	0.9 percent of oxygen saturation	Standard Deviation 2.99

Secondary

Change From Baseline in Peak VO2 Up to Week 52

Change from baseline in peak VO2 up to Week 52 was reported.

Time frame: Baseline up to Week 52

Population: FAS included all participants randomized to the study treatment.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Change From Baseline in Peak VO2 Up to Week 52	-0.92 mL/kg/min	Standard Error 0.296
Macitentan	Change From Baseline in Peak VO2 Up to Week 52	-0.31 mL/kg/min	Standard Error 0.293

Secondary

Change From Baseline in Prothrombin International Normalized Ratio

Change from baseline in prothrombin international normalized ratio was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Prothrombin International Normalized Ratio	Baseline	1.434 Ratio	Standard Deviation 0.7364
Placebo	Change From Baseline in Prothrombin International Normalized Ratio	Week 32	0.171 Ratio	Standard Deviation 0.9204
Placebo	Change From Baseline in Prothrombin International Normalized Ratio	Week 8	-0.009 Ratio	Standard Deviation 0.3216
Placebo	Change From Baseline in Prothrombin International Normalized Ratio	Week 52	-0.044 Ratio	Standard Deviation 0.3265
Placebo	Change From Baseline in Prothrombin International Normalized Ratio	Week 16	0.015 Ratio	Standard Deviation 0.3806
Macitentan	Change From Baseline in Prothrombin International Normalized Ratio	Week 52	-0.120 Ratio	Standard Deviation 0.3889
Macitentan	Change From Baseline in Prothrombin International Normalized Ratio	Baseline	1.516 Ratio	Standard Deviation 0.8014
Macitentan	Change From Baseline in Prothrombin International Normalized Ratio	Week 16	0.049 Ratio	Standard Deviation 1.1653
Macitentan	Change From Baseline in Prothrombin International Normalized Ratio	Week 32	0.033 Ratio	Standard Deviation 0.4597
Macitentan	Change From Baseline in Prothrombin International Normalized Ratio	Week 8	-0.054 Ratio	Standard Deviation 0.4652

Secondary

Change From Baseline in Prothrombin Time

Change from baseline in prothrombin time was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Prothrombin Time	Week 16	0.04 Seconds (sec)	Standard Deviation 3.921
Placebo	Change From Baseline in Prothrombin Time	Week 32	1.45 Seconds (sec)	Standard Deviation 8.261
Placebo	Change From Baseline in Prothrombin Time	Week 8	-0.23 Seconds (sec)	Standard Deviation 3.265
Placebo	Change From Baseline in Prothrombin Time	Week 52	-0.64 Seconds (sec)	Standard Deviation 3.167
Placebo	Change From Baseline in Prothrombin Time	Baseline	14.72 Seconds (sec)	Standard Deviation 7.033
Macitentan	Change From Baseline in Prothrombin Time	Week 52	-1.20 Seconds (sec)	Standard Deviation 3.567
Macitentan	Change From Baseline in Prothrombin Time	Baseline	15.37 Seconds (sec)	Standard Deviation 7.61
Macitentan	Change From Baseline in Prothrombin Time	Week 8	-0.53 Seconds (sec)	Standard Deviation 4.567
Macitentan	Change From Baseline in Prothrombin Time	Week 32	0.03 Seconds (sec)	Standard Deviation 4.135
Macitentan	Change From Baseline in Prothrombin Time	Week 16	0.36 Seconds (sec)	Standard Deviation 10.868

Secondary

Change From Baseline in Pulse Rate

Change from baseline in pulse rate at Week 8, Week 16, Week 32 and Week 52 was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Pulse Rate	Week 8	-3.9 beats per minute (bpm)	Standard Deviation 12.8
Placebo	Change From Baseline in Pulse Rate	Week 32	0.2 beats per minute (bpm)	Standard Deviation 12.37
Placebo	Change From Baseline in Pulse Rate	Week 16	0.1 beats per minute (bpm)	Standard Deviation 14.76
Placebo	Change From Baseline in Pulse Rate	Week 52	-0.7 beats per minute (bpm)	Standard Deviation 11.56
Placebo	Change From Baseline in Pulse Rate	Baseline	81.3 beats per minute (bpm)	Standard Deviation 12.52
Macitentan	Change From Baseline in Pulse Rate	Week 52	-2.9 beats per minute (bpm)	Standard Deviation 10.25
Macitentan	Change From Baseline in Pulse Rate	Baseline	78.2 beats per minute (bpm)	Standard Deviation 13.33
Macitentan	Change From Baseline in Pulse Rate	Week 8	-5.9 beats per minute (bpm)	Standard Deviation 12.07
Macitentan	Change From Baseline in Pulse Rate	Week 16	-0.1 beats per minute (bpm)	Standard Deviation 11.57
Macitentan	Change From Baseline in Pulse Rate	Week 32	1.1 beats per minute (bpm)	Standard Deviation 9.1

Secondary

Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)

Change from baseline in systolic and diastolic arterial BP at Week 8, Week 16, Week 32 and Week 52 was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Diastolic BP: Week 8	-0.2 millimeters of mercury (mmHg)	Standard Deviation 5.86
Placebo	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Systolic BP: Week 32	-6.3 millimeters of mercury (mmHg)	Standard Deviation 15.09
Placebo	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Diastolic BP: Week 16	-0.6 millimeters of mercury (mmHg)	Standard Deviation 10.06
Placebo	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Systolic BP: Week 16	0.5 millimeters of mercury (mmHg)	Standard Deviation 14.68
Placebo	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Baseline	116.0 millimeters of mercury (mmHg)	Standard Deviation 12.1
Placebo	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Diastolic BP: Week 32	1.3 millimeters of mercury (mmHg)	Standard Deviation 8.64
Placebo	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Systolic BP: Week 52	0.0 millimeters of mercury (mmHg)	Standard Deviation 12.12
Placebo	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Diastolic BP: Week 52	1.3 millimeters of mercury (mmHg)	Standard Deviation 10.84
Placebo	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Systolic BP: Week 8	2.5 millimeters of mercury (mmHg)	Standard Deviation 14.41
Macitentan	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Diastolic BP: Week 52	-2.8 millimeters of mercury (mmHg)	Standard Deviation 11.21
Macitentan	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Systolic BP: Week 8	-0.4 millimeters of mercury (mmHg)	Standard Deviation 11.67
Macitentan	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Systolic BP: Week 16	-4.6 millimeters of mercury (mmHg)	Standard Deviation 13.05
Macitentan	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Systolic BP: Week 32	-3.1 millimeters of mercury (mmHg)	Standard Deviation 10.51
Macitentan	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Systolic BP: Week 52	-4.8 millimeters of mercury (mmHg)	Standard Deviation 12.08
Macitentan	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Diastolic BP: Week 8	-0.1 millimeters of mercury (mmHg)	Standard Deviation 9.57
Macitentan	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Diastolic BP: Week 16	-3.1 millimeters of mercury (mmHg)	Standard Deviation 8.74
Macitentan	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Diastolic BP: Week 32	-1.4 millimeters of mercury (mmHg)	Standard Deviation 8.21
Macitentan	Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Baseline	117.0 millimeters of mercury (mmHg)	Standard Deviation 10.95

Secondary

Change From Baseline in Urate

Change from baseline in urate was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Urate	Week 8	-0.8 umol/L	Standard Deviation 40.76
Placebo	Change From Baseline in Urate	Week 32	16.0 umol/L	Standard Deviation 39.35
Placebo	Change From Baseline in Urate	Week 16	2.8 umol/L	Standard Deviation 40.13
Placebo	Change From Baseline in Urate	Week 52	1.1 umol/L	Standard Deviation 49.36
Placebo	Change From Baseline in Urate	Baseline	360.0 umol/L	Standard Deviation 70.95
Macitentan	Change From Baseline in Urate	Week 52	-25.8 umol/L	Standard Deviation 54.39
Macitentan	Change From Baseline in Urate	Baseline	372.7 umol/L	Standard Deviation 88.25
Macitentan	Change From Baseline in Urate	Week 8	-53.6 umol/L	Standard Deviation 40.17
Macitentan	Change From Baseline in Urate	Week 16	-37.8 umol/L	Standard Deviation 40.01
Macitentan	Change From Baseline in Urate	Week 32	-56.7 umol/L	Standard Deviation 53.18

Secondary

Change From Baseline in Urea Nitrogen

Change from baseline in urea nitrogen was reported.

Time frame: Baseline, Week 8, Week 16, Week 32 and Week 52

Population: Safety analysis set included all participants who received at least one dose of study treatment. Here n signifies number of participants evaluable at different timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Urea Nitrogen	Week 52	-0.06 millimoles per liter (mmol/L)	Standard Deviation 1.251
Placebo	Change From Baseline in Urea Nitrogen	Baseline	5.26 millimoles per liter (mmol/L)	Standard Deviation 1.402
Placebo	Change From Baseline in Urea Nitrogen	Week 8	-0.30 millimoles per liter (mmol/L)	Standard Deviation 0.989
Placebo	Change From Baseline in Urea Nitrogen	Week 16	-0.04 millimoles per liter (mmol/L)	Standard Deviation 1.043
Placebo	Change From Baseline in Urea Nitrogen	Week 32	0.02 millimoles per liter (mmol/L)	Standard Deviation 0.955
Macitentan	Change From Baseline in Urea Nitrogen	Week 32	-0.25 millimoles per liter (mmol/L)	Standard Deviation 1.274
Macitentan	Change From Baseline in Urea Nitrogen	Week 16	0.06 millimoles per liter (mmol/L)	Standard Deviation 1.278
Macitentan	Change From Baseline in Urea Nitrogen	Baseline	5.08 millimoles per liter (mmol/L)	Standard Deviation 1.35
Macitentan	Change From Baseline in Urea Nitrogen	Week 52	0.04 millimoles per liter (mmol/L)	Standard Deviation 1.101
Macitentan	Change From Baseline in Urea Nitrogen	Week 8	-0.09 millimoles per liter (mmol/L)	Standard Deviation 1.217

Secondary

Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment

Number of participants with AEs leading to premature discontinuation of study treatment was reported. AEs leading to premature discontinuation of study treatment were those with action taken with study drug reported as 'permanently discontinued' by the investigator.

Time frame: Up to 56 weeks

Population: Safety set included all participants who received at least one dose of study treatment.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Placebo	Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment	1 Participants
Macitentan	Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment	3 Participants

Secondary

Number of Participants With Treatment-emergent Adverse Events (AEs)

An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.

Time frame: Up to 56 weeks

Population: The Safety analysis set included all participants who received at least one dose of study treatment.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Placebo	Number of Participants With Treatment-emergent Adverse Events (AEs)	44 Participants
Macitentan	Number of Participants With Treatment-emergent Adverse Events (AEs)	48 Participants

Secondary

Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values

Number of participants with treatment-emergent markedly laboratory abnormal laboratory values were reported. Abnormal values for platelets (LL \< 75); Lymphocytes (HH \> 4.0); Neutrophils (LL \< 1.5); Prothrombin International Normalized Ratio: HH (greater than and equal to \[\>=\] 1.5 upper limit of normal \[ULN\]), Ratio: HH \>= 2.5 ULN); Bilirubin (HH \>= 2 ULN); Alkaline Phosphatase (HH \> 2.5 ULN); Glomerular Filtration Rate (LL \< 60); Glucose (HH \> 8.9); Triglycerides (HH \> 3.42). Here HH refers to values above the normal range, where H stands for high and LL refers to values below the normal range where L stands for low.

Time frame: Up to 56 weeks

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Neutrophils: LL (< 1.5)	0 Participants
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Alkaline Phosphatase: HH (> 2.5 ULN)	1 Participants
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Lymphocytes: HH (> 4.0)	0 Participants
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Glomerular Filtration Rate: LL (< 60)	1 Participants
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Prothrombin International Normalized Ratio: HH (>= 1.5 ULN)	3 Participants
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Glucose: LL (< 3.0)	0 Participants
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Platelets: LL (< 75)	2 Participants
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Glucose: HH (> 8.9)	0 Participants
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Prothrombin International Normalized Ratio: HH (>= 2.5 ULN)	1 Participants
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Triglycerides: HH (> 3.42)	3 Participants
Placebo	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Bilirubin: HH (>= 2 ULN)	1 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Triglycerides: HH (> 3.42)	1 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Bilirubin: HH (>= 2 ULN)	2 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Platelets: LL (< 75)	1 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Lymphocytes: HH (> 4.0)	1 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Neutrophils: LL (< 1.5)	2 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Prothrombin International Normalized Ratio: HH (>= 1.5 ULN)	5 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Prothrombin International Normalized Ratio: HH (>= 2.5 ULN)	1 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Alkaline Phosphatase: HH (> 2.5 ULN)	0 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Glomerular Filtration Rate: LL (< 60)	1 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Glucose: LL (< 3.0)	2 Participants
Macitentan	Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Glucose: HH (> 8.9)	2 Participants

Secondary

Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)

SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above.

Time frame: Up to 56 weeks

Population: The Safety analysis set included all participants who received at least one dose of study treatment.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Placebo	Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)	9 Participants
Macitentan	Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)	13 Participants

Source: ClinicalTrials.gov · Data processed: Feb 23, 2026

Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects

Conditions

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) Up to Week 16

Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)

Change From Baseline in Albumin and Protein

Change From Baseline in Alpha Fetoprotein

Change From Baseline in Bilirubin and Direct Bilirubin

Change From Baseline in Body Weight

Change From Baseline in Creatinine

Change From Baseline in Cystatin C

Change From Baseline in Erythrocytes and Reticulocytes

Change From Baseline in Gamma Glutamyl Transferase

Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium

Change From Baseline in Hematocrit

Change From Baseline in Hemoglobin

Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets

Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) Up to Week 16

Change From Baseline in Oxygen Saturation (SpO2)

Change From Baseline in Peak VO2 Up to Week 52

Change From Baseline in Prothrombin International Normalized Ratio

Change From Baseline in Prothrombin Time

Change From Baseline in Pulse Rate

Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)

Change From Baseline in Urate

Change From Baseline in Urea Nitrogen

Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment

Number of Participants With Treatment-emergent Adverse Events (AEs)

Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values

Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)