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Clinical Trial Results:
Prospective, Multi-center, Double-blind, Randomized, Active-controlled, Triple-dummy, Parallel-group, Group-sequential, Adaptive Phase 3 Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed Dose Combination in Subjects With Pulmonary Arterial Hypertension (PAH), Followed by an Open-label Treatment Period With Macitentan and Tadalafil Fixed Dose Combination Therapy

Summary
EudraCT number	2014-004786-25
Trial protocol	DE PL ES BG IT
Global end of trial date	27 Sep 2024

Results information
Results version number	v1(current)
This version publication date	23 Oct 2025
First version publication date	23 Oct 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AC-077A301

ISRCTN number

US NCT number

NCT03904693

WHO universal trial number (UTN)

Sponsor organisation name

Janssen-Cilag International NV

Sponsor organisation address

Turnhoutseweg 30, Beerse, Belgium, B-2340

Public contact

Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com

Scientific contact

Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

27 Sep 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

27 Sep 2024

Was the trial ended prematurely?

Main objective of the trial

The main objective of this trial was to evaluate the effect of the macitentan 10 milligrams (mg) and tadalafil 40 mg as a fixed dose combination (M/T FDC) vs macitentan 10 mg alone on pulmonary vascular resistance (PVR) at end of double-blind treatment (EDBT) in participants with symptomatic World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) who were PAH-specific treatment-naive or were currently treated with an endothelin receptor antagonists (ERA) as monotherapy and to evaluate the effect of the M/T FDC vs tadalafil 40 mg alone on PVR at EDBT in participants with symptomatic WHO Group 1 PAH who are PAH-specific treatment-naive or were currently treated with a phosphodiesterase type-5 inhibitor (PDE-5i) as monotherapy.

Protection of trial subjects

This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Oct 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Malaysia: 13

Country: Number of subjects enrolled

United States: 30

Country: Number of subjects enrolled

Germany: 13

Country: Number of subjects enrolled

Italy: 6

Country: Number of subjects enrolled

Poland: 12

Country: Number of subjects enrolled

Spain: 8

Country: Number of subjects enrolled

Türkiye: 17

Country: Number of subjects enrolled

Bulgaria: 4

Country: Number of subjects enrolled

Taiwan: 11

Country: Number of subjects enrolled

Brazil: 12

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

China: 23

Country: Number of subjects enrolled

Japan: 8

Country: Number of subjects enrolled

Mexico: 10

Country: Number of subjects enrolled

Russian Federation: 11

Country: Number of subjects enrolled

South Africa: 6

Worldwide total number of subjects

186

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

148

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 187 participants were enrolled and randomised, of whom 186 received treatment. Of these, 170 completed the treatment, and 177 completed the double-blind (DB) period. Among them, 169 entered the open-label (OL) extension and received treatment; 135 completed the treatment, and 144 participants completed the study.

Period 1 title

DB Treatment Period (Week 1 to Week 16)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg

Arm description

During double-blind treatment period, participants who were either treatment-naive or on a predefined stable dose of endothelin receptor antagonist (ERA), received one tablet of macitentan 10 mg along with two tablets of placebo matching to tadalafil 20 mg, orally, once daily at Weeks 1 and 2 (titration phase). From Week 3 to 16 (maintenance phase), participants continued to receive one tablet of macitentan 10 mg and two tablets placebo tablet matching to tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), orally, once daily.

Arm type

Active comparator

Investigational medicinal product name

Macitentan 10 mg

Investigational medicinal product code

ACT-064992

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received one tablet of macitentan 10 mg orally, once daily at Weeks 1 and 2 (titration phase) and from Week 3 to 16 (maintenance phase).

Investigational medicinal product name

Placebo matching to M/T FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received one tablet of placebo matching to M/T FDC, orally, once daily from Week 3 to 16 (maintenance phase).

Investigational medicinal product name

Placebo matching to Tadalafil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received two tablets of placebo matching to tadalafil 20 mg, orally, once daily at Weeks 1 and 2 (titration phase) and from Week 3 to 16 (maintenance phase).

DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg)

Arm description

During DB treatment period, participants who were either treatment-naive or on a predefined stable dose of phosphodiesterase type-5 inhibitor (PDE-5i), received one tablet (two tablets if already on allowable dose at baseline) of tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg and one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (titration phase). Participants further received two tablets of tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg, orally, once daily at Week 2 (titration phase). From Week 3 to 16 (maintenance phase), participants received two tablets of tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg and one tablet of placebo matching to M/T FDC, orally, once daily.

Arm type

Active comparator

Investigational medicinal product name

Tadalafil 20 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received one tablet (two tablets if already on allowable dose at baseline) of tadalafil 20 mg, orally, once daily at Week 1 (titration phase). Participants further received two tablets of tadalafil 20 mg, orally, once daily at Week 2 (titration phase) and from Week 3 to 16 (maintenance phase).

Investigational medicinal product name

Placebo matching to M/T FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received one tablet of placebo matching to M/T FDC, orally, once daily from Week 3 to 16 (maintenance phase).

Investigational medicinal product name

Placebo matching to Macitentan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received one tablet of placebo matching to macitentan 10 mg, orally, once daily at Week 1 and Week 2 (titration phase) and from Week 3 to 16 (maintenance phase).

DB: Treatment-naive/Prior ERA/ PDE-5i Strata: M/T FDC

Arm description

During double-blind treatment period, participants who were either treatment-naive or on a predefined stable dose of ERA or PDE-5i, received one tablet of macitentan 10 mg along with one tablet of tadalafil 20 mg and one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (uptitration phase). Participants further received one tablet of macitentan 10 mg along with two tablets of tadalafil 20 mg, orally, once daily at Week 2 (uptitration phase). From Week 3 to 16 (maintenance phase), participants received one tablet of placebo matching to macitentan 10 mg along with two tablets of placebo matching to tadalafil 20 mg and one tablet of macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), orally, once daily.

Arm type

Experimental

Investigational medicinal product name

Macitentan 10 mg

Investigational medicinal product code

ACT-064992

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received one tablet of macitentan 10 mg orally, once daily at Weeks 1 and 2 (titration phase).

Investigational medicinal product name

Tadalafil 20 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received one tablet of tadalafil 20 mg, orally, once daily at Week 1 (uptitration phase). Participants further received two tablets of tadalafil 20 mg, orally, once daily at Week 2 (uptitration phase).

Investigational medicinal product name

M/T FDC

Investigational medicinal product code

ACT-064992D

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received one tablet of M/T FDC, orally, once daily from Week 3 to 16 (maintenance phase).

Investigational medicinal product name

Placebo matching to Macitentan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received one tablet of placebo matching to macitentan 10 mg, orally, once daily from Week 3 to 16 (maintenance phase).

Investigational medicinal product name

Placebo matching to Tadalafil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (uptitration phase). From Week 3 to 16 (maintenance phase), participants received two tablets of placebo matching to tadalafil 20 mg, orally, once daily.

Number of subjects in period 1	DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg	DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg)	DB: Treatment-naive/Prior ERA/ PDE-5i Strata: M/T FDC
Started	35	44	107
Naive and Prior ERA Strata: M/T FDC	0 ^[1]	0 ^[2]	70 ^[3]
Naive and Prior PDE-5i Strata: M/T FDC	0 ^[4]	0 ^[5]	86 ^[6]
Completed	35	43	99
Not completed	0	1	8
Adverse event, serious fatal	-	-	2
Consent withdrawn by subject	-	1	4
Physician decision	-	-	2

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Only reported subjects were planned to be included in the milestone.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Only reported subjects were planned to be included in the milestone.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Only reported subjects were planned to be included in the milestone.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Only reported subjects were planned to be included in the milestone.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Only reported subjects were planned to be included in the milestone.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Only reported subjects were planned to be included in the milestone.

Period 2 title

OL Treatment Period (Week 17 to Week189)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

OL: Treatment-naive and Prior ERA Strata: M/T FDC

Arm description

After completion of DB phase, participants who were either treatment-naive or on a predefined stable dose of ERA and received macitentan monotherapy during DB phase entered open label (OL) phase. During the OL phase participants received one tablet of macitentan 10 mg along with one tablet of tadalafil 20 mg and one tablet of placebo matching tadalafil 20 mg, orally, once daily for first 7 days (Week 17, titration phase). Subsequently participants received two tablets of tadalafil 20 mg along with one tablet of macitentan 10 mg, orally, once daily for 7 days (Week 18, titration phase). From Weeks 19 to 183 (maintenance phase), participants continued to receive one tablet of M/T FDC, orally, once daily.

Arm type

Active comparator

Investigational medicinal product name

M/T FDC

Investigational medicinal product code

ACT-064992D

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the OL phase participants received one tablet of M/T FDC, orally, once daily from Weeks 19 to 183 (maintenance phase).

Investigational medicinal product name

Placebo matching Tadalafil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the OL phase participants received one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 17 (titration phase).

Investigational medicinal product name

Tadalafil 20 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the OL phase participants received one tablet of tadalafil 20 mg orally, once daily at Week 17 and Week 18 (titration phase).

Investigational medicinal product name

Macitentan 10 mg

Investigational medicinal product code

ACT-064992

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the OL phase participants received one tablet of macitentan 10 mg orally, once daily at Week 17 and Week 18 (titration phase).

OL: Treatment-naive and Prior PDE-5i Strata: M/T FDC

Arm description

After completion of DB phase, participants who were either treatment-naive or on a predefined stable dose of PDE-5i and received tadalafil monotherapy during DB phase entered OL phase. During the OL phase participants received one tablet of macitentan 10 mg along with two tablets of tadalafil 20 mg, orally, once daily for the first 2 weeks (Week 17 and Week 18; titration phase). From Weeks 19 to 183 (maintenance phase), participants continued to receive one tablet of M/T FDC, orally, once daily.

Arm type

Active comparator

Investigational medicinal product name

Macitentan 10 mg

Investigational medicinal product code

ACT-064992

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the OL phase participants received one tablet of macitentan 10 mg, orally, once daily for first 2 weeks (week 17 and Week 18; titration phase).

Investigational medicinal product name

Tadalafil 20 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the OL phase participants received two tablet of tadalafil 20 mg, orally, once daily for first 2 weeks (week 17 and Week 18; titration phase).

Investigational medicinal product name

M/T FDC

Investigational medicinal product code

ACT-064992D

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the OL phase participants received one tablet of M/T FDC, orally, once daily from Weeks 19 to 183 (maintenance phase).

OL: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC

Arm description

After completion of DB phase, participants who were either treatment-naive or on a predefined stable dose of ERA or PDE-5i and received M/T FDC during DB phase entered OL phase. During the OL phase participants received one tablet macitentan 10 mg along with two tablets of tadalafil 20 mg, orally, once daily for 2 weeks (Week 17 and Week 18; titration phase). From Weeks 19 to 183 (maintenance phase), participants continued to receive one tablet of M/T FDC, orally, once daily.

Arm type

Experimental

Investigational medicinal product name

M/T FDC

Investigational medicinal product code

ACT-064992D

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the OL phase participants received one tablet of M/T FDC, orally, once daily from Weeks 19 to 183 (maintenance phase).

Investigational medicinal product name

Tadalafil 20 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the OL phase participants received two tablet of tadalafil 20 mg, orally, once daily for first 2 weeks (week 17 and Week 18; titration phase).

Investigational medicinal product name

Macitentan 10 mg

Investigational medicinal product code

ACT-064992

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the OL phase participants received one tablet of macitentan 10 mg, orally, once daily for first 2 weeks (week 17 and Week 18; titration phase).

Number of subjects in period 2 ^[7]	OL: Treatment-naive and Prior ERA Strata: M/T FDC	OL: Treatment-naive and Prior PDE-5i Strata: M/T FDC	OL: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC
Started	35	43	91
Completed	30	38	76
Not completed	5	5	15
Adverse event, serious fatal	-	-	5
Consent withdrawn by subject	2	4	7
Adverse event, non-fatal	2	-	-
Initiated prohibited medication	1	-	-
Technical problems	-	-	1
Family problems	-	-	1
Noncompliance with study drug	-	1	-
Lost to follow-up	-	-	1

Notes
[7] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Only reported subjects were planned to be included in the current period.

Baseline characteristics

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Reporting group title

DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg

Reporting group description

Reporting group title

DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg)

Reporting group description

Reporting group title

DB: Treatment-naive/Prior ERA/ PDE-5i Strata: M/T FDC

Reporting group description

Reporting group values	DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg	DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg)	DB: Treatment-naive/Prior ERA/ PDE-5i Strata: M/T FDC	Total
Number of subjects	35	44	107
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	51.3 ( 15.85 )	53.1 ( 13.66 )	48.7 ( 15.78 )	-
Gender categorical
Units: Subjects
Male	6	10	25	41
Female	29	34	82	145

End points

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Reporting group title

DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg

Reporting group description

Reporting group title

DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg)

Reporting group description

Reporting group title

DB: Treatment-naive/Prior ERA/ PDE-5i Strata: M/T FDC

Reporting group description

Reporting group title

OL: Treatment-naive and Prior ERA Strata: M/T FDC

Reporting group description

Reporting group title

OL: Treatment-naive and Prior PDE-5i Strata: M/T FDC

Reporting group description

Reporting group title

OL: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC

Reporting group description

Subject analysis set title

DB: Treatmentnaive And Prior ERA Strata: M/T FDC

Subject analysis set type

Sub-group analysis

Subject analysis set description

During double-blind treatment period, participants who were either treatment-naive or on a predefined stable dose of ERA, received one tablet of macitentan 10 mg along with one tablet of tadalafil 20 mg and one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (uptitration phase). Participants further received one tablet of macitentan 10 mg along with two tablets of tadalafil 20 mg, orally, once daily at Week 2 (uptitration phase). From Week 3 to 16 (maintenance phase), participants received one tablet of placebo matching to macitentan 10 mg along with two tablets of placebo matching to tadalafil 20 mg and one tablet of macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), orally, once daily.

Subject analysis set title

DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC

Subject analysis set type

Sub-group analysis

Subject analysis set description

During double-blind treatment period, participants who were either treatment-naive or on a predefined stable dose of PDE-5i, received one tablet of macitentan 10 mg along with one tablet of tadalafil 20 mg and one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (uptitration phase). Participants further received one tablet of macitentan 10 mg along with two tablets of tadalafil 20 mg, orally, once daily at Week 2 (uptitration phase). From Week 3 to 16 (maintenance phase), participants received one tablet of placebo matching to macitentan 10 mg along with two tablets of placebo matching to tadalafil 20 mg and one tablet of macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), orally, once daily.

Primary: Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline

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End point title

Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline ^[1]

End point description

Change in PVR expressed as the ratio of geometric means of EDBT to baseline were reported. The full analysis set (FAS) included all randomised participants who received at least one dose of study treatment (for participants on FDC, at least one dose of either macitentan or tadalafil). Treatment-naive participants randomised to both macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC) arms (ERA and PDE-5i strata) were counted twice as per planned analysis.

End point type

Primary

End point timeframe

Baseline, EDBT (up to 16 weeks)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be analysed for specified baseline arms only.

End point values	DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg	DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg)	DB: Treatmentnaive And Prior ERA Strata: M/T FDC	DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC
Number of subjects analysed	35	44	70	86
Units: Ratio
geometric mean (confidence interval 95%)	0.77 (0.69 to 0.87)	0.78 (0.72 to 0.84)	0.55 (0.50 to 0.60)	0.56 (0.52 to 0.60)

Statistical Analysis 1

Comparison groups

DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg v DB: Treatmentnaive And Prior ERA Strata: M/T FDC

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Geometric Mean Ratio

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

0.82

Statistical Analysis 2

Comparison groups

DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg) v DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Geometric Mean Ratio

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

0.8

Secondary: Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD)

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End point title

Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD) ^[2]

End point description

Change from baseline to EDBT in 6MWD were reported. 6MWD was measured by 6-minute walk test (6MWT). The test measured the distance an individual was able to walk over a total of six minutes on a hard, flat surface with no obstacles. The goal was for the individual to walk as far as possible in 6 minutes. The FAS included all randomised participants who received at least one dose of study treatment (for participants on FDC, at least one dose of either macitentan or tadalafil). Treatment-naive participants randomised to both M/T FDC arms (ERA and PDE-5i strata) were counted twice as per planned analysis.

End point type

Secondary

End point timeframe

Baseline, EDBT (Week 16)

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be analysed for specified baseline arms only.

End point values	DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg	DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg)	DB: Treatmentnaive And Prior ERA Strata: M/T FDC	DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC
Number of subjects analysed	35	44	70	86
Units: Meters
arithmetic mean (standard deviation)	38.5 ( 70.42 )	15.9 ( 45.04 )	52.9 ( 88.23 )	43.4 ( 78.03 )

Statistical Analysis 4

Comparison groups

DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg) v DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0591

Method

ANCOVA

Parameter type

Geometric Mean Ratio

Point estimate

25.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.93

upper limit

51.59

Statistical Analysis 3

Comparison groups

DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg v DB: Treatmentnaive And Prior ERA Strata: M/T FDC

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3802

Method

ANCOVA

Parameter type

Geometric Mean Ratio

Point estimate

16.04

Confidence interval

level

95%

sides

2-sided

lower limit

-17

upper limit

49.08

Secondary: Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT

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End point title

Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT ^[3]

End point description

PAH-SYMPACT was a pulmonary arterial hypertension (PAH)-specific patient-reported outcomes questionnaire that consists of 11 symptoms items, 11 impacts items and 1 item on oxygen use. The symptom items were divided into cardiopulmonary and cardiovascular domains, and the impact items were divided into physical and emotional/cognitive domains. Cardiopulmonary symptoms contain 6 items; shortness of breath, fatigue, lack of energy, swelling in ankles or legs, swelling in stomach area, and cough. Scores for the individual items were reported on a 5-point Likert scale, ranging from 0 (no symptom at all) to 4 (very severe symptoms), with higher scores indicated greater symptom severity. The PAH-SYMPACT symptoms analysis set included all participants included in the FAS for whom at least one baseline value of symptoms domain was provided. Treatment-naive participants randomised to both M/T FDC arms (ERA and PDE-5i strata) were counted twice as per planned analysis.

End point type

Secondary

End point timeframe

Baseline, EDBT (Week 16)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be analysed for specified baseline arms only.

End point values	DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg	DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg)	DB: Treatmentnaive And Prior ERA Strata: M/T FDC	DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC
Number of subjects analysed	33	42	66	81
Units: Score on a scale
arithmetic mean (standard deviation)	-0.14 ( 0.478 )	-0.13 ( 0.554 )	-0.20 ( 0.394 )	-0.15 ( 0.404 )

No statistical analyses for this end point

Secondary: Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT

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End point title

Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT ^[4]

End point description

PAHSYMPACT is a PAH-specific patient-reported outcomes questionnaire that consists of 11 symptoms items, 11 impacts items and 1 item on oxygen use. The symptom items were divided into cardiopulmonary and cardiovascular domains, and the impact items were divided into physical and emotional/cognitive domains. Cardiovascular symptoms contain 5 items; heart palpitations (heart fluttering), rapid heartbeat, chest pain, chest tightness, and lightheadedness. Scores for the individual items were reported on a 5-point Likert scale, ranging from 0 (no symptom at all) to 4 (very severe symptom), with higher scores indicated greater symptom severity. The PAH-SYMPACT symptoms analysis set included all participants included in the FAS for whom at least one baseline value of symptoms domain was provided. Treatment-naive participants randomised to both M/T FDC arms (ERA and PDE-5i strata) were counted twice as per planned analysis.

End point type

Secondary

End point timeframe

Baseline, EDBT (Week 16)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be analysed for specified baseline arms only.

End point values	DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg	DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg)	DB: Treatmentnaive And Prior ERA Strata: M/T FDC	DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC
Number of subjects analysed	33	42	66	81
Units: Score on a scale
arithmetic mean (standard deviation)	-0.14 ( 0.473 )	-0.18 ( 0.612 )	-0.15 ( 0.349 )	-0.10 ( 0.318 )

No statistical analyses for this end point

Secondary: Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT

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End point title

Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT ^[5]

End point description

Percentage of participants with absence of worsening in FC from baseline at EDBT were reported. Study was adaptive with 2 stages: Stage 1 and Stage 2. WHO functional classification (FC), PAH range from Class I (no limitation in physical activity, no dyspnea or fatigue, chest pain, or near syncope with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity), Class IV (cannot perform a physical activity without any symptoms, dyspnea and/or fatigue at rest). The FAS included all randomised participants who received at least one dose of study treatment (for participants on FDC, at least one dose of either macitentan or tadalafil). Treatment-naive participants randomised to both M/T FDC arms (ERA and PDE-5i strata) were counted twice as per planned analysis. Here, 'N' (overall number of participants analysed) signifies the number of participants evaluable and "n" number of participants evaluable for specified category.

End point type

Secondary

End point timeframe

At Week 16 (EDBT)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data was planned to be analysed for specified baseline arms only.

End point values	DB: Treatment-naive/Prior ERA Strata (S): Macitentan 10mg	DB: Treatment-naive/Prior PDE-5i S :Tadalafil 20 mg(2*20 mg)	DB: Treatmentnaive And Prior ERA Strata: M/T FDC	DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC
Number of subjects analysed	18	22	38	47
Units: Percentage of participants
number (not applicable)
Stage: 1 : Class I (n=18, 22, 47, 38)	5.6	4.5	5.3	12.8
Stage: I : Class II (n=18, 38, 22, 47)	55.6	63.6	57.9	59.6
Stage: I : Class III (n=18, 38, 22, 47, 38)	38.9	31.8	23.7	25.5
Stage: I : Class IV (n=18, , 38, 22, 47)	0	0	0	0
Stage: 1 : Missing (n=18, , 38, 22, 47)	0	13.2	13.2	2.1
Stage: 2 : Class I (n=17, 32, 22, 39)	11.8	9.1	9.4	7.7
Stage: 2 : Class II (n=17, 32, 22, 39)	52.9	54.5	75.0	61.5
Stage: 2 : Class III (n=17, 32, 22, 39)	35.3	36.4	15.6	25.6
Stage: 2 : Class IV (n=17, 32, 22, 39)	0	0	0	0
Stage: 2 : Missing (n=17, 32, 22, 39)	0	0	0	5.1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

DB phase: From Day 1 to Week 16; OL phase: From Week 16 up to 35 days after last dose (Week 189)

Adverse event reporting additional description

DB: all treated. OL: combination safety set: participants in M/T FDC in DB and received M/T FDC in DB and those who received M/T FDC in OL. Treatment naive participants in both M/T FDC arms (ERA/PDE-5i strata) counted twice per planned analysis. For participants treated with M/T FDC in DB, combined data from DB and OL was analyzed in OL period.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

DB: Treatment-naive and Prior ERA Strata: Macitentan 10 mg

Reporting group description

During double-blind (DB) treatment period, participants who were either treatment-naive or on a predefined stable dose of endothelin receptor antagonist (ERA), received one tablet of macitentan 10 mg along with two tablets of placebo matching to tadalafil 20 mg, orally, once daily at Weeks 1 and 2 (titration phase). From Week 3 to 16 (maintenance phase), participants continued to receive one tablet of macitentan 10 mg and two tablets placebo tablet matching to tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), orally, once daily.

Reporting group title

DB: Treatment-naive And Prior ERA Strata: M/T FDC

Reporting group description

During DB treatment period, participants who were either treatment-naive or on a predefined stable dose of ERA, received one tablet of macitentan 10 mg along with one tablet of tadalafil 20 mg and one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (uptitration phase). Participants further received one tablet of macitentan 10 mg along with two tablets of tadalafil 20 mg, orally, once daily at Week 2 (uptitration phase). From Week 3 to 16 (maintenance phase), participants received one tablet of placebo matching to macitentan 10 mg along with two tablets of placebo matching to tadalafil 20 mg and one tablet of macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), orally, once daily.

Reporting group title

DB:Treatment-naive/PriorPDE-5i Strata:Tadalafil 20mg(2*20 mg)

Reporting group description

During double-blind treatment period, participants who were either treatment-naive or on a predefined stable dose of phosphodiesterase type-5 inhibitor (PDE-5i), received one tablet (two tablets if already on allowable dose at baseline) of tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg and one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (titration phase). Participants further received two tablets of tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg, orally, once daily at Week 2 (titration phase). From Week 3 to 16 (maintenance phase), participants received two tablets of tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg and one tablet of placebo matching to M/T FDC, orally, once daily.

Reporting group title

DB: Treatment-naive And Prior PDE-5i strata: M/T FDC

Reporting group description

During DB treatment period, participants who were either treatment-naive or on a predefined stable dose of PDE-5i, received one tablet of macitentan 10 mg along with one tablet of tadalafil 20 mg and one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (uptitration phase). Participants further received one tablet of macitentan 10 mg along with two tablets of tadalafil 20 mg, orally, once daily at Week 2 (uptitration phase). From Week 3 to 16 (maintenance phase), participants received one tablet of placebo matching to macitentan 10 mg along with two tablets of placebo matching to tadalafil 20 mg and one tablet of macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), orally, once daily.

Reporting group title

DB: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC

Reporting group description

During DB treatment period, participants who were either treatment-naive or on a predefined stable dose of ERA or PDE-5i, received one tablet of macitentan 10 mg along with one tablet of tadalafil 20 mg and one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (uptitration phase). Participants further received one tablet of macitentan 10 mg along with two tablets of tadalafil 20 mg, orally, once daily at Week 2 (uptitration phase). From Week 3 to 16 (maintenance phase), participants received one tablet of placebo matching to macitentan 10 mg along with two tablets of placebo matching to tadalafil 20 mg and one tablet of macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), orally, once daily.

Reporting group title

OL: Treatment-naive and Prior ERA Strata: M/T FDC

Reporting group description

Reporting group title

OL: Treatment-naive and Prior PDE-5i Strata: M/T FDC

Reporting group description

Reporting group title

DB + OL: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC

Reporting group description

During DB phase, participants who were either treatment-naive or on predefined stable dose of ERA/PDE-5i, received macitentan 10mg with tadalafil 20mg and placebo matching to tadalafil 20mg orally once daily(QD) at Week 1(uptitration phase). Participants received one tablet of macitentan 10mg with two tablets of tadalafil 20mg orally QD at Week 2 (uptitration phase). From Week 3-16 (maintenance phase), participants received one tablet of placebo matching to macitentan 10mg and two tablets matching to tadalafil 20mg and one tablet of M/T FDC orally once daily. After completion of DB phase, participants who were either treatment-naive or on a predefined stable dose of ERA/PDE-5i and received M/T FDC during DB phase entered OL phase. During OL phase participants received one tablet macitentan 10mg along with two tablets of tadalafil 20mg orally QD at Weeks 17,18 (titration phase). From Weeks 19-183 (maintenance phase), participants continued with one tablet of M/T FDC orally QD.

Serious adverse events	DB: Treatment-naive and Prior ERA Strata: Macitentan 10 mg	DB: Treatment-naive And Prior ERA Strata: M/T FDC	DB:Treatment-naive/PriorPDE-5i Strata:Tadalafil 20mg(2*20 mg)	DB: Treatment-naive And Prior PDE-5i strata: M/T FDC	DB: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC	OL: Treatment-naive and Prior ERA Strata: M/T FDC	OL: Treatment-naive and Prior PDE-5i Strata: M/T FDC	DB + OL: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 35 (8.57%)	11 / 70 (15.71%)	4 / 44 (9.09%)	12 / 86 (13.95%)	15 / 107 (14.02%)	10 / 35 (28.57%)	13 / 43 (30.23%)	39 / 107 (36.45%)
number of deaths (all causes)	0	2	0	2	3	0	2	9
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate Cancer
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	2 / 107 (1.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucinous Cystadenocarcinoma Ovary
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast Cancer
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest Pain
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral Swelling
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Swelling Face
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometrial Hyperplasia
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intermenstrual Bleeding
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian Cyst Ruptured
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine Polyp
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	1 / 44 (2.27%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	2 / 86 (2.33%)	2 / 107 (1.87%)	0 / 35 (0.00%)	0 / 43 (0.00%)	4 / 107 (3.74%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Autoimmune Lung Disease
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	1 / 35 (2.86%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Failure
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	2 / 107 (1.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
Pulmonary Veno-Occlusive Disease
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Arterial Hypertension
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	2 / 107 (1.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Jaw Fracture
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus Fracture
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur Fracture
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Patella Fracture
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural Haematoma
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina Pectoris
subjects affected / exposed	1 / 35 (2.86%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cor Pulmonale
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary Artery Disease
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac Failure
subjects affected / exposed	0 / 35 (0.00%)	2 / 70 (2.86%)	1 / 44 (2.27%)	1 / 86 (1.16%)	2 / 107 (1.87%)	0 / 35 (0.00%)	0 / 43 (0.00%)	2 / 107 (1.87%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Atrial Flutter
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	1 / 43 (2.33%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial Fibrillation
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Left Ventricular Failure
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	1 / 35 (2.86%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	2 / 107 (1.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Right Ventricular Failure
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	1 / 35 (2.86%)	1 / 43 (2.33%)	4 / 107 (3.74%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Sinus Node Dysfunction
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular Tachycardia
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Epilepsy
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral Infarction
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	1 / 44 (2.27%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Horner's Syndrome
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Normochromic Anaemia
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal Vein Occlusion
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis Ischaemic
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoidal Haemorrhage
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus Hernia
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper Gastrointestinal Haemorrhage
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tongue Cyst
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	0 / 86 (0.00%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal Ulcer
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	1 / 44 (2.27%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large Intestine Polyp
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varices Oesophageal
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic Cirrhosis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Portal Hypertension
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glomerulonephritis Membranous
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal Impairment
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Greater Trochanteric Pain Syndrome
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic Scleroderma
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	0 / 86 (0.00%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral Disc Protrusion
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	2 / 35 (5.71%)	1 / 43 (2.33%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess Bacterial
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Covid-19 Pneumonia
subjects affected / exposed	1 / 35 (2.86%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	2 / 107 (1.87%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Covid-19
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	5 / 107 (4.67%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis Clostridial
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
Influenza
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	0 / 86 (0.00%)	1 / 107 (0.93%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Parainfluenzae Virus Infection
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	1 / 35 (2.86%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 35 (2.86%)	0 / 70 (0.00%)	1 / 44 (2.27%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	3 / 107 (2.80%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia Viral
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhinovirus Infection
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral Upper Respiratory Tract Infection
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	1 / 43 (2.33%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal Bacteraemia
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	0 / 35 (0.00%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	DB: Treatment-naive and Prior ERA Strata: Macitentan 10 mg	DB: Treatment-naive And Prior ERA Strata: M/T FDC	DB:Treatment-naive/PriorPDE-5i Strata:Tadalafil 20mg(2*20 mg)	DB: Treatment-naive And Prior PDE-5i strata: M/T FDC	DB: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC	OL: Treatment-naive and Prior ERA Strata: M/T FDC	OL: Treatment-naive and Prior PDE-5i Strata: M/T FDC	DB + OL: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC
Total subjects affected by non serious adverse events
subjects affected / exposed	16 / 35 (45.71%)	49 / 70 (70.00%)	31 / 44 (70.45%)	58 / 86 (67.44%)	72 / 107 (67.29%)	28 / 35 (80.00%)	38 / 43 (88.37%)	89 / 107 (83.18%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	2 / 35 (5.71%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0
Vascular disorders
Flushing
subjects affected / exposed	2 / 35 (5.71%)	3 / 70 (4.29%)	0 / 44 (0.00%)	3 / 86 (3.49%)	3 / 107 (2.80%)	0 / 35 (0.00%)	0 / 43 (0.00%)	4 / 107 (3.74%)
occurrences all number	2	3	0	3	3	0	0	4
Hypotension
subjects affected / exposed	0 / 35 (0.00%)	5 / 70 (7.14%)	0 / 44 (0.00%)	4 / 86 (4.65%)	7 / 107 (6.54%)	1 / 35 (2.86%)	1 / 43 (2.33%)	9 / 107 (8.41%)
occurrences all number	0	5	0	4	7	1	1	10
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 35 (2.86%)	2 / 70 (2.86%)	1 / 44 (2.27%)	2 / 86 (2.33%)	3 / 107 (2.80%)	0 / 35 (0.00%)	0 / 43 (0.00%)	7 / 107 (6.54%)
occurrences all number	1	2	1	2	3	0	0	9
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 35 (0.00%)	2 / 70 (2.86%)	3 / 44 (6.82%)	2 / 86 (2.33%)	3 / 107 (2.80%)	0 / 35 (0.00%)	1 / 43 (2.33%)	3 / 107 (2.80%)
occurrences all number	0	2	4	2	3	0	1	3
Pyrexia
subjects affected / exposed	0 / 35 (0.00%)	2 / 70 (2.86%)	0 / 44 (0.00%)	4 / 86 (4.65%)	4 / 107 (3.74%)	0 / 35 (0.00%)	5 / 43 (11.63%)	7 / 107 (6.54%)
occurrences all number	0	3	0	6	6	0	5	11
Peripheral Swelling
subjects affected / exposed	1 / 35 (2.86%)	6 / 70 (8.57%)	0 / 44 (0.00%)	6 / 86 (6.98%)	6 / 107 (5.61%)	1 / 35 (2.86%)	0 / 43 (0.00%)	7 / 107 (6.54%)
occurrences all number	2	6	0	6	6	1	0	7
Oedema Peripheral
subjects affected / exposed	4 / 35 (11.43%)	9 / 70 (12.86%)	5 / 44 (11.36%)	12 / 86 (13.95%)	14 / 107 (13.08%)	1 / 35 (2.86%)	5 / 43 (11.63%)	16 / 107 (14.95%)
occurrences all number	4	11	6	15	18	1	7	21
Respiratory, thoracic and mediastinal disorders
Nasal Congestion
subjects affected / exposed	0 / 35 (0.00%)	3 / 70 (4.29%)	0 / 44 (0.00%)	3 / 86 (3.49%)	4 / 107 (3.74%)	1 / 35 (2.86%)	2 / 43 (4.65%)	6 / 107 (5.61%)
occurrences all number	0	3	0	3	4	1	2	6
Dyspnoea
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	2 / 44 (4.55%)	2 / 86 (2.33%)	2 / 107 (1.87%)	0 / 35 (0.00%)	7 / 43 (16.28%)	5 / 107 (4.67%)
occurrences all number	0	1	2	2	2	0	7	5
Cough
subjects affected / exposed	1 / 35 (2.86%)	5 / 70 (7.14%)	2 / 44 (4.55%)	6 / 86 (6.98%)	6 / 107 (5.61%)	2 / 35 (5.71%)	5 / 43 (11.63%)	11 / 107 (10.28%)
occurrences all number	1	5	2	6	6	2	5	12
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	2 / 35 (5.71%)	0 / 43 (0.00%)	2 / 107 (1.87%)
occurrences all number	0	0	0	0	0	2	0	2
Investigations
Blood Glucose Increased
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	2 / 35 (5.71%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Haemoglobin Decreased
subjects affected / exposed	0 / 35 (0.00%)	3 / 70 (4.29%)	0 / 44 (0.00%)	8 / 86 (9.30%)	8 / 107 (7.48%)	4 / 35 (11.43%)	1 / 43 (2.33%)	13 / 107 (12.15%)
occurrences all number	0	4	0	9	9	5	1	16
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 35 (2.86%)	1 / 70 (1.43%)	2 / 44 (4.55%)	2 / 86 (2.33%)	3 / 107 (2.80%)	1 / 35 (2.86%)	3 / 43 (6.98%)	7 / 107 (6.54%)
occurrences all number	3	1	2	2	3	1	4	7
Nervous system disorders
Headache
subjects affected / exposed	6 / 35 (17.14%)	12 / 70 (17.14%)	6 / 44 (13.64%)	14 / 86 (16.28%)	18 / 107 (16.82%)	3 / 35 (8.57%)	2 / 43 (4.65%)	23 / 107 (21.50%)
occurrences all number	7	16	6	16	23	4	2	31
Dizziness
subjects affected / exposed	1 / 35 (2.86%)	2 / 70 (2.86%)	1 / 44 (2.27%)	3 / 86 (3.49%)	3 / 107 (2.80%)	2 / 35 (5.71%)	1 / 43 (2.33%)	6 / 107 (5.61%)
occurrences all number	1	2	1	3	3	3	1	6
Blood and lymphatic system disorders
Iron Deficiency Anaemia
subjects affected / exposed	1 / 35 (2.86%)	2 / 70 (2.86%)	1 / 44 (2.27%)	2 / 86 (2.33%)	2 / 107 (1.87%)	0 / 35 (0.00%)	2 / 43 (4.65%)	6 / 107 (5.61%)
occurrences all number	1	2	1	2	2	0	2	7
Leukopenia
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	1 / 86 (1.16%)	1 / 107 (0.93%)	2 / 35 (5.71%)	0 / 43 (0.00%)	3 / 107 (2.80%)
occurrences all number	0	1	0	1	1	2	0	3
Thrombocytopenia
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	2 / 35 (5.71%)	1 / 43 (2.33%)	2 / 107 (1.87%)
occurrences all number	0	0	0	0	0	3	1	2
Anaemia
subjects affected / exposed	0 / 35 (0.00%)	6 / 70 (8.57%)	0 / 44 (0.00%)	6 / 86 (6.98%)	8 / 107 (7.48%)	4 / 35 (11.43%)	5 / 43 (11.63%)	13 / 107 (12.15%)
occurrences all number	0	8	0	7	10	5	5	17
Gastrointestinal disorders
Gastrooesophageal Reflux Disease
subjects affected / exposed	1 / 35 (2.86%)	0 / 70 (0.00%)	1 / 44 (2.27%)	1 / 86 (1.16%)	1 / 107 (0.93%)	3 / 35 (8.57%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences all number	1	0	1	1	1	3	0	1
Haemorrhoids
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	0 / 86 (0.00%)	1 / 107 (0.93%)	2 / 35 (5.71%)	0 / 43 (0.00%)	3 / 107 (2.80%)
occurrences all number	0	1	0	0	1	2	0	3
Nausea
subjects affected / exposed	0 / 35 (0.00%)	5 / 70 (7.14%)	3 / 44 (6.82%)	4 / 86 (4.65%)	6 / 107 (5.61%)	1 / 35 (2.86%)	1 / 43 (2.33%)	8 / 107 (7.48%)
occurrences all number	0	5	4	4	6	1	1	11
Vomiting
subjects affected / exposed	0 / 35 (0.00%)	3 / 70 (4.29%)	2 / 44 (4.55%)	4 / 86 (4.65%)	4 / 107 (3.74%)	0 / 35 (0.00%)	2 / 43 (4.65%)	9 / 107 (8.41%)
occurrences all number	0	3	3	4	4	0	5	10
Gastritis
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	2 / 86 (2.33%)	2 / 107 (1.87%)	3 / 35 (8.57%)	0 / 43 (0.00%)	4 / 107 (3.74%)
occurrences all number	0	0	0	2	2	3	0	4
Diarrhoea
subjects affected / exposed	0 / 35 (0.00%)	4 / 70 (5.71%)	6 / 44 (13.64%)	5 / 86 (5.81%)	5 / 107 (4.67%)	0 / 35 (0.00%)	2 / 43 (4.65%)	7 / 107 (6.54%)
occurrences all number	0	4	7	5	5	0	2	7
Dyspepsia
subjects affected / exposed	0 / 35 (0.00%)	4 / 70 (5.71%)	3 / 44 (6.82%)	4 / 86 (4.65%)	4 / 107 (3.74%)	0 / 35 (0.00%)	1 / 43 (2.33%)	4 / 107 (3.74%)
occurrences all number	0	4	3	4	4	0	2	6
Musculoskeletal and connective tissue disorders
Pain in Extremity
subjects affected / exposed	0 / 35 (0.00%)	2 / 70 (2.86%)	4 / 44 (9.09%)	2 / 86 (2.33%)	3 / 107 (2.80%)	1 / 35 (2.86%)	1 / 43 (2.33%)	6 / 107 (5.61%)
occurrences all number	0	2	4	2	3	1	1	6
Myalgia
subjects affected / exposed	0 / 35 (0.00%)	5 / 70 (7.14%)	2 / 44 (4.55%)	4 / 86 (4.65%)	6 / 107 (5.61%)	5 / 35 (14.29%)	2 / 43 (4.65%)	7 / 107 (6.54%)
occurrences all number	0	5	2	4	6	6	2	7
Intervertebral Disc Protrusion
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	0 / 86 (0.00%)	1 / 107 (0.93%)	2 / 35 (5.71%)	0 / 43 (0.00%)	1 / 107 (0.93%)
occurrences all number	0	2	0	0	2	2	0	2
Back Pain
subjects affected / exposed	1 / 35 (2.86%)	5 / 70 (7.14%)	4 / 44 (9.09%)	3 / 86 (3.49%)	5 / 107 (4.67%)	2 / 35 (5.71%)	2 / 43 (4.65%)	7 / 107 (6.54%)
occurrences all number	1	5	6	3	5	3	2	7
Arthralgia
subjects affected / exposed	2 / 35 (5.71%)	2 / 70 (2.86%)	4 / 44 (9.09%)	4 / 86 (4.65%)	4 / 107 (3.74%)	3 / 35 (8.57%)	3 / 43 (6.98%)	8 / 107 (7.48%)
occurrences all number	2	2	4	4	4	3	5	8
Infections and infestations
Sinusitis
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	1 / 44 (2.27%)	1 / 86 (1.16%)	1 / 107 (0.93%)	2 / 35 (5.71%)	1 / 43 (2.33%)	2 / 107 (1.87%)
occurrences all number	0	1	1	1	1	2	2	2
Nasopharyngitis
subjects affected / exposed	1 / 35 (2.86%)	1 / 70 (1.43%)	0 / 44 (0.00%)	3 / 86 (3.49%)	3 / 107 (2.80%)	2 / 35 (5.71%)	2 / 43 (4.65%)	7 / 107 (6.54%)
occurrences all number	1	1	0	3	3	3	8	11
Covid-19
subjects affected / exposed	2 / 35 (5.71%)	1 / 70 (1.43%)	2 / 44 (4.55%)	2 / 86 (2.33%)	2 / 107 (1.87%)	7 / 35 (20.00%)	10 / 43 (23.26%)	25 / 107 (23.36%)
occurrences all number	2	1	2	2	2	9	11	26
Suspected Covid-19
subjects affected / exposed	0 / 35 (0.00%)	0 / 70 (0.00%)	0 / 44 (0.00%)	0 / 86 (0.00%)	0 / 107 (0.00%)	2 / 35 (5.71%)	0 / 43 (0.00%)	0 / 107 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Urinary Tract Infection
subjects affected / exposed	0 / 35 (0.00%)	2 / 70 (2.86%)	0 / 44 (0.00%)	0 / 86 (0.00%)	2 / 107 (1.87%)	2 / 35 (5.71%)	4 / 43 (9.30%)	6 / 107 (5.61%)
occurrences all number	0	2	0	0	2	2	4	7
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 35 (0.00%)	2 / 70 (2.86%)	0 / 44 (0.00%)	1 / 86 (1.16%)	2 / 107 (1.87%)	5 / 35 (14.29%)	6 / 43 (13.95%)	5 / 107 (4.67%)
occurrences all number	0	2	0	1	2	5	6	7
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 35 (0.00%)	1 / 70 (1.43%)	0 / 44 (0.00%)	2 / 86 (2.33%)	2 / 107 (1.87%)	3 / 35 (8.57%)	1 / 43 (2.33%)	4 / 107 (3.74%)
occurrences all number	0	1	0	2	2	4	1	4
Hyperuricaemia
subjects affected / exposed	1 / 35 (2.86%)	4 / 70 (5.71%)	1 / 44 (2.27%)	4 / 86 (4.65%)	4 / 107 (3.74%)	0 / 35 (0.00%)	0 / 43 (0.00%)	4 / 107 (3.74%)
occurrences all number	1	4	1	4	4	0	0	5

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Were there any global substantial amendments to the protocol? Yes

12 Aug 2019

The purpose of this amendment was to meet 1. eligibility criteria for hemodynamics will be confirmed by the central reading, 2. change the objective of the evaluation of PAH symptoms and their impact on participant’s life from secondary to “other” objective, 3. update frequency of liver function test monitoring, 4. update plan for follow-up of participants who prematurely discontinue study treatment.

28 Feb 2020

The purpose of this amendment was to implement updated guidelines for the right heart catheterization and 6-minute walk test (6MWT) procedures in order to facilitate alignment in Right heart catheterization (RHC) and 6MWT procedures and data collection across all Actelion trials.

17 Jul 2020

The purpose of this amendment was to update an exclusion criteria and concomitant therapy section pertaining to newly identified drug-drug interactions (DDI) between macitentan and fluconazole (a dual moderate inhibitor of CYP3A4 and CYP2C9) from a pre-clinical study on implications of role of CYP2C9 in the metabolism of macitentan.

20 Oct 2020

The purpose of this amendment was to move the cardiopulmonary and cardiovascular domain scores of the Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) from exploratory endpoints to secondary endpoints following discussion with the Food and Drug Administration (FDA).

27 Apr 2021

The purpose of this amendment was to change the requirements on the minimum number of participants in each stratum (that is, treatment-naive, prior endothelin receptor antagonists [ERA]; prior- Phosphodiesterase type-5 inhibitor [PDE5i]) at the interim and final analyses.

21 Nov 2022

The purpose of this amendment was to capture participant experience while on one tablet of macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), a semi- structured qualitative interview sub study was assessed the participant's experience with study treatment, with regard to satisfaction with treatment regimen and adherence to treatment.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline

Primary: Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline

Secondary: Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD)

Secondary: Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD)

Secondary: Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT

Secondary: Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT

Secondary: Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT

Secondary: Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT

Secondary: Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT

Secondary: Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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