Trial Outcomes & Findings for The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (NCT NCT02558231)

Last Updated: 2025-03-30

Results Overview

Change from baseline to Week 26 in PVR was expressed as the ratio of Week 26 to baseline PVR value (Week 26 divided by baseline) using re-calculated PVR. PVR was determined by right heart catheterization (RHC). A geometric least square mean ratio of Week 26 to baseline PVR less than (\<) 1 corresponds to a reduction in PVR from baseline. Missing values were imputed using a last observation carried forward (LOCF) approach.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

247 participants

Primary outcome timeframe

Baseline, Week 26

Results posted on

2025-03-30

Participant Flow

Participant milestones

Participant milestones
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Overall Study STARTED	123	124
Overall Study Treated	123	123
Overall Study COMPLETED	98	98
Overall Study NOT COMPLETED	25	26

Reasons for withdrawal

Reasons for withdrawal
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Overall Study Death	4	12
Overall Study Lost to Follow-up	7	4
Overall Study Withdrawal by Subject	7	4
Overall Study Physician Decision	7	5
Overall Study Sponsor Decision	0	1

Baseline Characteristics

The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=123 Number Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=124 Number Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Total n=247 Number Total of all reporting groups
Age, Continuous	52.2 years STANDARD_DEVIATION 13.48 • n=93 Participants	51.6 years STANDARD_DEVIATION 13.92 • n=4 Participants	51.9 years STANDARD_DEVIATION 13.67 • n=27 Participants
Sex: Female, Male Female	93 Participants n=93 Participants	94 Participants n=4 Participants	187 Participants n=27 Participants
Sex: Female, Male Male	30 Participants n=93 Participants	30 Participants n=4 Participants	60 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants n=93 Participants	10 Participants n=4 Participants	20 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	106 Participants n=93 Participants	108 Participants n=4 Participants	214 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	7 Participants n=93 Participants	6 Participants n=4 Participants	13 Participants n=27 Participants
Race/Ethnicity, Customized Black or African American	5 participants n=93 Participants	5 participants n=4 Participants	10 participants n=27 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 participants n=93 Participants	0 participants n=4 Participants	1 participants n=27 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 participants n=93 Participants	0 participants n=4 Participants	0 participants n=27 Participants
Race/Ethnicity, Customized Asian	7 participants n=93 Participants	3 participants n=4 Participants	10 participants n=27 Participants
Race/Ethnicity, Customized White	102 participants n=93 Participants	108 participants n=4 Participants	210 participants n=27 Participants
Race/Ethnicity, Customized Other	3 participants n=93 Participants	3 participants n=4 Participants	6 participants n=27 Participants
Race/Ethnicity, Customized Unknown or Not Reported	5 participants n=93 Participants	5 participants n=4 Participants	10 participants n=27 Participants
Region of Enrollment AUSTRALIA	2 participants n=93 Participants	2 participants n=4 Participants	4 participants n=27 Participants
Region of Enrollment AUSTRIA	9 participants n=93 Participants	5 participants n=4 Participants	14 participants n=27 Participants
Region of Enrollment BELGIUM	2 participants n=93 Participants	5 participants n=4 Participants	7 participants n=27 Participants
Region of Enrollment CANADA	11 participants n=93 Participants	14 participants n=4 Participants	25 participants n=27 Participants
Region of Enrollment DENMARK	3 participants n=93 Participants	2 participants n=4 Participants	5 participants n=27 Participants
Region of Enrollment FRANCE	4 participants n=93 Participants	5 participants n=4 Participants	9 participants n=27 Participants
Region of Enrollment GERMANY	13 participants n=93 Participants	23 participants n=4 Participants	36 participants n=27 Participants
Region of Enrollment IRELAND	1 participants n=93 Participants	0 participants n=4 Participants	1 participants n=27 Participants
Region of Enrollment ITALY	5 participants n=93 Participants	6 participants n=4 Participants	11 participants n=27 Participants
Region of Enrollment NETHERLANDS	2 participants n=93 Participants	2 participants n=4 Participants	4 participants n=27 Participants
Region of Enrollment SPAIN	2 participants n=93 Participants	1 participants n=4 Participants	3 participants n=27 Participants
Region of Enrollment SWEDEN	7 participants n=93 Participants	0 participants n=4 Participants	7 participants n=27 Participants
Region of Enrollment SWITZERLAND	1 participants n=93 Participants	1 participants n=4 Participants	2 participants n=27 Participants
Region of Enrollment UNITED KINGDOM	3 participants n=93 Participants	2 participants n=4 Participants	5 participants n=27 Participants
Region of Enrollment UNITED STATES	58 participants n=93 Participants	56 participants n=4 Participants	114 participants n=27 Participants

PRIMARY outcome

Timeframe: Baseline, Week 26

Population: Full analysis set (FAS) included all randomized participants.

Outcome measures

Outcome measures
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=123 Participants Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=124 Participants Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR)	0.46 ratio Interval 0.422 to 0.503	0.48 ratio Interval 0.441 to 0.526

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure.

The change from baseline to Week 26 in 6MWD was calculated as Week 26 minus baseline. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. Missing values were imputed using a LOCF approach.

Outcome measures

Outcome measures
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=123 Participants Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=121 Participants Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD)	54.96 meter Interval 40.419 to 69.501	56.39 meter Interval 41.447 to 71.327

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure.

The change from baseline to Week 26 in NT-proBNP was expressed as the ratio of Week 26 to baseline NT-proBNP (Week 26 divided by baseline). A geometric least square mean ratio of Week 26 to baseline NT-proBNP \<1 corresponds to a reduction in NT-proBNP from baseline. Missing values were imputed using a LOCF approach.

Outcome measures

Outcome measures
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=121 Participants Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=122 Participants Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels	0.26 ratio Interval 0.206 to 0.328	0.25 ratio Interval 0.2 to 0.32

SECONDARY outcome

Timeframe: Week 26

Population: FAS included all randomized participants. Here, N (number of participants analyzed) signifies number of participants analyzed for this outcome measure. Participants with WHO FC IV at baseline were excluded from this analysis as they could not shift to a worse category.

WHO FC is a classification graded from Class I to IV which reflects disease severity based on symptoms. Worsening was defined as death or hospitalization due to PAH. Class I: No limitation of activity; Class II: slight limitation with ordinary activities; Class III: may not have symptoms at rest but greatly limited activities; Class IV: symptoms at rest and inability to carry out any physical activity without symptoms. Missing values were imputed using a LOCF approach.

Outcome measures

Outcome measures
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=122 Participants Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=119 Participants Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC)	99.2 percentage of participants	97.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Full analysis set included all randomized participants.

Change from baseline to Week 26 in mean Pulmonary Arterial Pressure (mPAP) was measured. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Missing values were imputed using a LOCF approach.

Outcome measures

Outcome measures
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=123 Participants Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=124 Participants Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP)	-12.92 millimeters of mercury (mmHg) Interval -14.609 to -11.235	-12.20 millimeters of mercury (mmHg) Interval -13.881 to -10.515

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure.

Change from baseline to Week 26 in mean Right Atrial Pressure (mRAP) was measured. Missing values were imputed using a LOCF approach.

Outcome measures

Outcome measures
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=123 Participants Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=123 Participants Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP)	-1.78 mmHg Interval -2.512 to -1.045	-1.69 mmHg Interval -2.429 to -0.955

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Full analysis set included all randomized participants.

Change from baseline to Week 26 in total pulmonary resistance was measured. Total pulmonary resistance was calculated as mPAP/CO\*80, where CO is cardiac output. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach.

Outcome measures

Outcome measures
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=123 Participants Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=124 Participants Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Change From Baseline to Week 26 in Total Pulmonary Resistance	-511.88 dynes*second per centimeter^5 Interval -569.36 to -454.4	-514.28 dynes*second per centimeter^5 Interval -571.45 to -457.11

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Full analysis set included all randomized participants.

Change from baseline to Week 26 in cardiac index was measured. Cardiac index is the amount of blood pumped by the heart, per minute, per meter square of body surface area. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach.

Outcome measures

Outcome measures
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=123 Participants Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=124 Participants Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Change From Baseline to Week 26 in Cardiac Index	0.97 liters per minute per meter square Interval 0.814 to 1.13	0.84 liters per minute per meter square Interval 0.684 to 0.997

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure.

Change from baseline to Week 26 in venous oxygen saturation was measured. Missing values were imputed using a LOCF approach.

Outcome measures

Outcome measures
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=120 Participants Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=118 Participants Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Change From Baseline to Week 26 in Venous Oxygen Saturation (%)	5.59 percentage of oxygen saturation Interval 4.37 to 6.801	6.79 percentage of oxygen saturation Interval 5.561 to 8.02

SECONDARY outcome

Timeframe: Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months)

Population: Full analysis set included all randomized participants.

Number of participants with disease progression event were reported. Disease progression event as adjudicated by the CEC, defined as any of the following: a. Death (all causes; adjudicated for PAH relationship); b. Hospitalization for worsening PAH; c. Initiation of prostacyclin, a prostacyclin analog, or a prostacyclin receptor agonist for worsening PAH; d. Clinical worsening defined as a post-baseline decrease in 6MWD by more than (\>) 15 percent (%) from the highest 6MWD obtained at or after baseline, accompanied by WHO FC III or IV (both conditions confirmed at two consecutive post-baseline visits separated by 1-21 days).

Outcome measures

Outcome measures
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=123 Participants Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=124 Participants Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Number of Participants With Disease Progression Event Week 26	8 Participants	13 Participants
Number of Participants With Disease Progression Event Month 12	13 Participants	20 Participants
Number of Participants With Disease Progression Event Month 18	15 Participants	23 Participants
Number of Participants With Disease Progression Event Month 24	15 Participants	25 Participants
Number of Participants With Disease Progression Event Month 30	16 Participants	27 Participants
Number of Participants With Disease Progression Event End of Analysis Period (up to 40 months)	16 Participants	27 Participants

Adverse Events

Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)

Serious events: 58 serious events

Other events: 118 other events

Deaths: 4 deaths

Double Oral Therapy (Macitentan, Tadalafil, and Placebo)

Serious events: 48 serious events

Other events: 119 other events

Deaths: 12 deaths

Serious adverse events

Other adverse events

Additional Information

Principal Clinical Scientist

Actelion Pharmaceuticals Ltd.

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER

Serious adverse events
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=119 participants at risk Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=127 participants at risk Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Surgical and medical procedures Penile Operation	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Surgical and medical procedures Pericardial Drainage	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Surgical and medical procedures Therapy Change	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Vascular disorders Deep Vein Thrombosis	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	1.6% 2/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Vascular disorders Hypertensive Crisis	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Vascular disorders Hypotension	1.7% 2/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	1.6% 2/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Vascular disorders Paradoxical Embolism	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Vascular disorders Shock	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Acute Left Ventricular Failure	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Acute Right Ventricular Failure	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Atrial Tachycardia	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Cardiac Failure	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Cardiac Failure Acute	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Cardiac Failure Congestive	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Cardiac Failure High Output	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Cardiogenic Shock	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Coronary Artery Disease	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	1.6% 2/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Sinus Tachycardia	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Intestinal Ischaemia	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Oesophageal Haemorrhage	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Retroperitoneal Haemorrhage	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Infections and infestations Appendicitis	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Injury, poisoning and procedural complications Hip Fracture	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Investigations Cardiac Electrophysiologic Study	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Investigations Transplant Evaluation	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Metabolism and nutrition disorders Failure to Thrive	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Metabolism and nutrition disorders Fluid Overload	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Metabolism and nutrition disorders Hypertriglyceridaemia	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Metabolism and nutrition disorders Malnutrition	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast Cancer	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung Carcinoma Cell Type Unspecified Stage I	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Respiratory, thoracic and mediastinal disorders Pulmonary Hypertension	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Surgical and medical procedures Toe Amputation	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Vascular disorders Hypertension	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Vascular disorders Shock Haemorrhagic	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Blood and lymphatic system disorders Anaemia	2.5% 3/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	1.6% 2/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Blood and lymphatic system disorders Blood Loss Anaemia	0.84% 1/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.00% 0/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Blood and lymphatic system disorders Febrile Neutropenia	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Blood and lymphatic system disorders Iron Deficiency Anaemia	2.5% 3/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Blood and lymphatic system disorders Leukopenia	0.00% 0/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.

Other adverse events
Measure	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) n=119 participants at risk Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	Double Oral Therapy (Macitentan, Tadalafil, and Placebo) n=127 participants at risk Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
Blood and lymphatic system disorders Anaemia	11.8% 14/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	8.7% 11/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Blood and lymphatic system disorders Iron Deficiency Anaemia	5.0% 6/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	3.9% 5/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Cardiac disorders Palpitations	11.8% 14/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	8.7% 11/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Abdominal Distension	5.0% 6/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	3.1% 4/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Abdominal Pain	5.9% 7/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	4.7% 6/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Abdominal Pain Upper	6.7% 8/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	5.5% 7/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Constipation	5.9% 7/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	7.1% 9/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Diarrhoea	55.5% 66/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	32.3% 41/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Dyspepsia	22.7% 27/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	13.4% 17/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Gastrooesophageal Reflux Disease	9.2% 11/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	14.2% 18/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Nausea	47.1% 56/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	26.0% 33/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Gastrointestinal disorders Vomiting	25.2% 30/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	11.0% 14/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
General disorders Chest Discomfort	5.9% 7/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	7.9% 10/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
General disorders Chest Pain	5.0% 6/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	3.1% 4/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
General disorders Chills	5.9% 7/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	1.6% 2/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
General disorders Fatigue	20.2% 24/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	17.3% 22/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
General disorders Non-Cardiac Chest Pain	8.4% 10/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	4.7% 6/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
General disorders Oedema Peripheral	37.8% 45/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	36.2% 46/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
General disorders Pain	9.2% 11/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	7.1% 9/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
General disorders Peripheral Swelling	9.2% 11/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	3.1% 4/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
General disorders Pyrexia	9.2% 11/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	8.7% 11/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Infections and infestations Bronchitis	5.0% 6/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	4.7% 6/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Infections and infestations Influenza	5.0% 6/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	5.5% 7/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Infections and infestations Nasopharyngitis	16.8% 20/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	18.1% 23/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Infections and infestations Upper Respiratory Tract Infection	11.8% 14/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	16.5% 21/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Infections and infestations Urinary Tract Infection	7.6% 9/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	8.7% 11/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Investigations Alanine Aminotransferase Increased	6.7% 8/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	3.1% 4/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Investigations Aspartate Aminotransferase Increased	8.4% 10/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	3.1% 4/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Investigations Haemoglobin Decreased	8.4% 10/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	4.7% 6/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Investigations Weight Increased	4.2% 5/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	6.3% 8/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Metabolism and nutrition disorders Decreased Appetite	11.8% 14/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	3.1% 4/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Metabolism and nutrition disorders Fluid Retention	5.0% 6/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	6.3% 8/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Metabolism and nutrition disorders Hypokalaemia	14.3% 17/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	11.8% 15/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Musculoskeletal and connective tissue disorders Arthralgia	16.0% 19/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	15.0% 19/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Musculoskeletal and connective tissue disorders Back Pain	10.9% 13/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	15.0% 19/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Musculoskeletal and connective tissue disorders Muscle Spasms	7.6% 9/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	5.5% 7/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	6.7% 8/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	0.79% 1/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Musculoskeletal and connective tissue disorders Myalgia	17.6% 21/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	15.0% 19/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Musculoskeletal and connective tissue disorders Pain in Extremity	31.1% 37/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	18.9% 24/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.
Musculoskeletal and connective tissue disorders Pain in Jaw	29.4% 35/119 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.	11.8% 15/127 • Up to 42 Months The Safety Set included all participants who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy= 123 participants and Double oral therapy= 123 participants). Four participants in triple therapy group did not receive selexipag and were therefore allocated to the double therapy group for the safety analyses.