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Clinical Trial Results:
A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Rodatristat Ethyl in Patients with Pulmonary Arterial Hypertension

Summary
EudraCT number	2020-004971-42
Trial protocol	DE LV FR BE CZ PL IT BG ES AT
Global end of trial date	28 Aug 2023

Results information
Results version number	v1(current)
This version publication date	01 Feb 2026
First version publication date	01 Feb 2026
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

RVT-1201-2002

ISRCTN number

-

US NCT number

NCT04712669

WHO universal trial number (UTN)

-

Other trial identifiers

IND: 126945

Sponsor organisation name

Altavant Sciences GmbH

Sponsor organisation address

6501 Weston Parkway, Cary, United States,

Public contact

Information Desk, Altavant Sciences GmbH, clinicaltrials@altavant.com

Scientific contact

Information Desk, Altavant Sciences GmbH, clinicaltrials@altavant.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

26 Sep 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

05 Jun 2023

Global end of trial reached?

Yes

Global end of trial date

28 Aug 2023

Was the trial ended prematurely?

Yes

Main objective of the trial

To evaluate the effect of rodatristat ethyl on the percent change from baseline of pulmonary vascular resistance (PVR), as measured by right heart catheterization (RHC) in patients with PAH.

Protection of trial subjects

An external, multidisciplinary, Independent Data Monitoring Committee (IDMC) will review the progress of the study and perform interim reviews of unblinded safety and efficacy data at regular intervals and provide recommendations to the Sponsor whether the nature, frequency, and severity of AEs and AESIs associated with IP warrant the early termination of the study in the best interests of the subjects, whether the study should continue as planned, or whether the study should continue with modifications. The Clinical Endpoint Adjudication Committee (CEAC) including three Pulmonary Arterial Hypertension (PAH) expert physicians will adjudicate the clinical worsening events (CWEs) per Clinical Endpoint Adjudication Charter. The RHC data will be adjudicated by the blinded medical monitors per the RHC Adjudication Process Document.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

15 Mar 2021

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

78 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 2

Country: Number of subjects enrolled

Spain: 5

Country: Number of subjects enrolled

Austria: 1

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Bulgaria: 1

Country: Number of subjects enrolled

Czechia: 3

Country: Number of subjects enrolled

France: 12

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Italy: 6

Country: Number of subjects enrolled

Latvia: 12

Country: Number of subjects enrolled

United States: 44

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Bosnia and Herzegovina: 1

Country: Number of subjects enrolled

Moldova, Republic of: 12

Worldwide total number of subjects

108

EEA total number of subjects

47

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

78

From 65 to 84 years

30

85 years and over

0

Subject disposition

Top of page

Recruitment details

Approximately ninety (90) patients will be enrolled. Patients will be randomized 1:1:1 to placebo, 300 mg BID, or 600 mg BID of rodatristat ethyl. Patients who complete the Main Study will have the option to enroll into an OLE and continue to receive rodatristat ethyl.

Screening details

The study will consist of a Screening Period (up to 28 days in duration)

Period 1 title

Main Study

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

At the Baseline Visit, eligible patients will be randomly allocated (1:1:1) to one of the following 3 treatment groups. In order to maintain the study blind, patients will take 2 tablets in the morning and 2 tablets in the evening in one of the combinations.

Are arms mutually exclusive

Yes

Rodatristat Ethyl 300 mg BID

Arm description

MAIN study: Rodatristat ethyl 300 mg and placebo tablet BID + standard of care medication(s) taken for 24 weeks

Arm type

Experimental

Investigational medicinal product name

Rodatristat ethyl

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

One 300 mg tablet will be taken BID with food, approximately 12 hours apart.

Rodatristat Ethyl 600 mg BID

Arm description

MAIN study:Rodatristat ethyl two 300 mg tablets BID + standard of care medication(s) taken for 24 weeks

Arm type

Experimental

Investigational medicinal product name

Rodatristat ethyl

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Two 300 mg tablet will be taken BID with food, approximately 12 hours apart.

Placebo

Arm description

MAIN study: Matching two placebo tablets BID+ standard of care medication(s) taken for 24 weeks

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Two tablets of Placebo will be taken BID with food, approximately 12 hours apart.

Number of subjects in period 1	Rodatristat Ethyl 300 mg BID	Rodatristat Ethyl 600 mg BID	Placebo
Started	36	36	36
Completed	28	26	32
Not completed	8	10	4
Termination by Sponsor	-	-	1
Physician decision	1	-	-
Consent withdrawn by subject	3	6	-
Adverse event, non-fatal	4	4	3

Period 2 title

Open Label Extension Phase

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo-Rodatristat Ethyl 300 mg

Arm description

Subjects whose actual treatment group is Placebo in the double-blind phase (Main Study) and received Rodatristat ethyl two 300 mg tablets BID in the open-label phase

Arm type

Experimental

Investigational medicinal product name

Rodatristat ethyl

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

One 300 mg tablet will be taken BID with food, approximately 12 hours apart.

Placebo-Rodatristat Ethyl 600 mg

Arm description

Subjects whose actual treatment group is Placebo in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase

Arm type

Experimental

Investigational medicinal product name

Rodatristat ethyl

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Two 300 mg tablet will be taken BID with food, approximately 12 hours apart.

Rodatristat Ethyl 300 mg-Rodatristat Ethyl 300 mg

Arm description

Subjects whose actual treatment group is Rodatristat ethyl two 300 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 300 mg tablets BID in the open-label phase

Arm type

Experimental

Investigational medicinal product name

Rodatristat ethyl

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

One 300 mg tablet will be taken BID with food, approximately 12 hours apart.

Rodatristat Ethyl 300 mg-Rodatristat Ethyl 600 mg

Arm description

Subjects whose actual treatment group is Rodatristat ethyl two 300 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase

Arm type

Experimental

Investigational medicinal product name

Rodatristat ethyl

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Two 300 mg tablet will be taken BID with food, approximately 12 hours apart.

Rodatristat Ethyl 600 mg-Rodatristat Ethyl 600 mg

Arm description

Subjects whose actual treatment group is Rodatristat ethyl two 600 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase

Arm type

Experimental

Investigational medicinal product name

Rodatristat ethyl

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Two 300 mg tablet will be taken BID with food, approximately 12 hours apart.

Investigational medicinal product name

Rodatristat ethyl

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Two 300 mg tablet will be taken BID with food, approximately 12 hours apart.

Number of subjects in period 2 ^[1]	Placebo-Rodatristat Ethyl 300 mg	Placebo-Rodatristat Ethyl 600 mg	Rodatristat Ethyl 300 mg-Rodatristat Ethyl 300 mg	Rodatristat Ethyl 300 mg-Rodatristat Ethyl 600 mg	Rodatristat Ethyl 600 mg-Rodatristat Ethyl 600 mg
Started	15	16	22	2	21
Completed	0	0	0	0	0
Not completed	15	16	22	2	21
Termination by Sponsor	11	9	14	-	14
Adverse event, serious fatal	1	-	-	-	-
Physician decision	1	-	-	-	-
Consent withdrawn by subject	1	5	5	-	4
Adverse event, non-fatal	1	1	3	1	2
Lost to follow-up	-	-	-	1	1
Lack of efficacy	-	1	-	-	-

Notes
[1] - 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: Not all participants completing Main Study are required to participate in Open Label Extension phase. Some participants choose not to participate in Open Label Extension Phase

Baseline characteristics

Top of page

Reporting group title

Rodatristat Ethyl 300 mg BID

Reporting group description

MAIN study: Rodatristat ethyl 300 mg and placebo tablet BID + standard of care medication(s) taken for 24 weeks

Reporting group title

Rodatristat Ethyl 600 mg BID

Reporting group description

MAIN study:Rodatristat ethyl two 300 mg tablets BID + standard of care medication(s) taken for 24 weeks

Reporting group title

Placebo

Reporting group description

MAIN study: Matching two placebo tablets BID+ standard of care medication(s) taken for 24 weeks

Reporting group values	Rodatristat Ethyl 300 mg BID	Rodatristat Ethyl 600 mg BID	Placebo	Total
Number of subjects	36	36	36	108
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	0	0	0	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Between 18 and 65 years	32	29	27	88
>=65 years	4	7	9	20
Age continuous
Units: years
arithmetic mean (standard deviation)	56.4 ( 14.3 )	48.4 ( 15.31 )	53.7 ( 13.76 )	-
Gender categorical
Units: Subjects
Female	28	31	26	85
Male	8	5	10	23
Race
Units: Subjects
American Indian or Alaska Native	1	0	0	1
Asian	1	1	2	4
Native Hawaiian or Other Pacific Islander	0	0	0	0
White	29	29	25	83
More than one race	0	0	0	0
Unknown or Not Reported	5	5	7	17
Black or African American	0	1	2	3
Ethnicity
Units: Subjects
Hispanic or Latino	4	5	2	11
Not Hispanic or Latino	32	29	33	94
Unknown or Not Reported	0	2	1	3

End points

Top of page

Reporting group title

Rodatristat Ethyl 300 mg BID

Reporting group description

MAIN study: Rodatristat ethyl 300 mg and placebo tablet BID + standard of care medication(s) taken for 24 weeks

Reporting group title

Rodatristat Ethyl 600 mg BID

Reporting group description

MAIN study:Rodatristat ethyl two 300 mg tablets BID + standard of care medication(s) taken for 24 weeks

Reporting group title

Placebo

Reporting group description

MAIN study: Matching two placebo tablets BID+ standard of care medication(s) taken for 24 weeks

Reporting group title

Placebo-Rodatristat Ethyl 300 mg

Reporting group description

Subjects whose actual treatment group is Placebo in the double-blind phase (Main Study) and received Rodatristat ethyl two 300 mg tablets BID in the open-label phase

Reporting group title

Placebo-Rodatristat Ethyl 600 mg

Reporting group description

Subjects whose actual treatment group is Placebo in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase

Reporting group title

Rodatristat Ethyl 300 mg-Rodatristat Ethyl 300 mg

Reporting group description

Subjects whose actual treatment group is Rodatristat ethyl two 300 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 300 mg tablets BID in the open-label phase

Reporting group title

Rodatristat Ethyl 300 mg-Rodatristat Ethyl 600 mg

Reporting group description

Subjects whose actual treatment group is Rodatristat ethyl two 300 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase

Reporting group title

Rodatristat Ethyl 600 mg-Rodatristat Ethyl 600 mg

Reporting group description

Subjects whose actual treatment group is Rodatristat ethyl two 600 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase

Subject analysis set title

Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who receive any amount of study drug.

Subject analysis set title

ITT Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomized into any one of treatment groups.

Primary: Percent change from baseline of pulmonary vascular resistance (PVR) at Week 24

Top of page

End point title

Percent change from baseline of pulmonary vascular resistance (PVR) at Week 24

End point description

Pulmonary vascular resistance (PVR) was measured by right heart catheterization (RHC)

End point type

Primary

End point timeframe

24 Weeks

End point values	Rodatristat Ethyl 300 mg BID	Rodatristat Ethyl 600 mg BID	Placebo	ITT Population
Number of subjects analysed	36	36	36	72
Units: percent
least squares mean (standard error)	63.083 ( 18.529 )	64.219 ( 18.013 )	5.813 ( 18.052 )	63.651 ( 13.268 )

Percent change from baseline

Statistical analysis description

Percent change from baseline of pulmonary vascular resistance (PVR) at Week 24. H0: The mean change from baseline in PVR at Week 24 is equal between placebo and rodatristat ethyl.

Comparison groups

Rodatristat Ethyl 300 mg BID v Placebo

Number of subjects included in analysis

72

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0208 ^[1]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

57.27

Confidence interval

level

95%

sides

2-sided

lower limit

8.716

upper limit

105.824

Variability estimate

Standard error of the mean

Dispersion value

24.773

Notes
[1] - LSM, SE, CIs for each treatment group; LSM Diff, SE, CIs, and p-value are estimated using an ANCOVA model incl. factors for treatment group and randomization strata with associated baseline value as a covariate.

Secondary: Change from baseline in World Health Organization (WHO) Functional Class (FC)

Top of page

End point title

Change from baseline in World Health Organization (WHO) Functional Class (FC)

End point description

PAH functional disease severity is classified according to World Health Organization (WHO) Functional Class (FC). Patients are classified into 1 of 4 functional classes on the basis of their degree of physical limitation and associated symptoms.

End point type

Secondary

End point timeframe

24 Weeks

End point values	Rodatristat Ethyl 300 mg BID	Rodatristat Ethyl 600 mg BID	Placebo	ITT Population
Number of subjects analysed	36	36	36	72
Units: Count of Participants
-II	0	0	0	0
-I	2	3	3	5
No Change	30	30	30	60
+I	4	3	3	7
+II	0	0	0	0

No statistical analyses for this end point

Secondary: Change from baseline in six-minute walk distance (6MWD)

Top of page

End point title

Change from baseline in six-minute walk distance (6MWD)

End point description

The six-minute walk distance (6MWD) is a simple, commonly used, standardized measure of functional exercise capacity and endurance. It is a commonly used measure of efficacy in PAH clinical studies.

End point type

Secondary

End point timeframe

24 Weeks

End point values	Rodatristat Ethyl 300 mg BID	Rodatristat Ethyl 600 mg BID	Placebo	ITT Population
Number of subjects analysed	36	36	36	72
Units: six-minute walk distance (6MWD) (meters)
median (inter-quartile range (Q1-Q3))	-14.5 (-31.5 to 28)	0 (-27.5 to 20)	2.5 (-13.5 to 23)	-4.25 (-31.0 to 25.0)

No statistical analyses for this end point

Secondary: Change from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels

Top of page

End point title

Change from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels

End point description

N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is a strong predictor of disease progression and mortality in PAH patients. Current PAH treatment guidelines recommend measurement of NT-proBNP levels for both risk assessment and longitudinal follow up. NT-proBNP levels are also a good marker of response to treatment.

End point type

Secondary

End point timeframe

24 Weeks

End point values	Rodatristat Ethyl 300 mg BID	Rodatristat Ethyl 600 mg BID	Placebo	ITT Population
Number of subjects analysed	36	36	36	72
Units: pg/mL
least squares mean (standard error)	1145.7 ( 325.93 )	886.1 ( 275.7 )	19.8 ( 143.86 )	1015.9 ( 215.25 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Up to 48 weeks

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24

Reporting group title

Rodatristat Ethyl 300 mg BID

Reporting group description

MAIN study: Rodatristat ethyl 300 mg and placebo tablet BID + standard of care medication(s) taken for 24 weeks

Reporting group title

Placebo

Reporting group description

-

Reporting group title

Rodatristat Ethyl 600 mg BID

Reporting group description

MAIN study : Rodatristat ethyl two 300 mg tablets BID + standard of care medication(s) taken for 24 weeks

Reporting group title

Rodatristat Ethyl 300 mg-Rodatristat Ethyl 600 mg

Reporting group description

Subjects whose actual treatment group is Rodatristat ethyl two 300 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase

Reporting group title

Rodatristat Ethyl 300 mg-Rodatristat Ethyl 300 mg

Reporting group description

Subjects whose actual treatment group is Rodatristat ethyl two 300 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 300 mg tablets BID in the open-label phase

Reporting group title

Placebo-Rodatristat Ethyl 600 mg

Reporting group description

Subjects whose actual treatment group is Placebo in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase

Reporting group title

Rodatristat Ethyl 600 mg-Rodatristat Ethyl 600 mg

Reporting group description

Subjects whose actual treatment group is Rodatristat ethyl two 600 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase

Reporting group title

Placebo-Rodatristat Ethyl 300 mg

Reporting group description

Subjects whose actual treatment group is Placebo in the double-blind phase (Main Study) and received Rodatristat ethyl two 300 mg tablets BID in the open-label phase

Serious adverse events	Rodatristat Ethyl 300 mg BID	Placebo	Rodatristat Ethyl 600 mg BID	Rodatristat Ethyl 300 mg-Rodatristat Ethyl 600 mg	Rodatristat Ethyl 300 mg-Rodatristat Ethyl 300 mg	Placebo-Rodatristat Ethyl 600 mg	Rodatristat Ethyl 600 mg-Rodatristat Ethyl 600 mg	Placebo-Rodatristat Ethyl 300 mg
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 36 (25.00%)	1 / 36 (2.78%)	6 / 36 (16.67%)	0 / 2 (0.00%)	6 / 22 (27.27%)	4 / 16 (25.00%)	3 / 21 (14.29%)	2 / 15 (13.33%)
number of deaths (all causes)	1	0	0	0	0	0	0	2
number of deaths resulting from adverse events	1	0	0	0	0	0	0	2
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Anticoagulation drug level below therapeutic
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Transplant evaluation
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	1 / 21 (4.76%)	0 / 15 (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
Alanine aminotransferase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Right ventricular failure
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	2 / 22 (9.09%)	1 / 16 (6.25%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 2	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Angina pectoris
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Atrial fibrillation
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Myocardial infarction
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Nervous system disorders
Seizure
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Presyncope
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	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
Syncope
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	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
General disorders and administration site conditions
Device related thrombosis
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	1 / 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
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Pyrexia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (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
Sudden Death
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
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 / 1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (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
Diarrhoea
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 36 (2.78%)	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	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
Pulmonary arterial hypertension
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	2 / 36 (5.56%)	0 / 2 (0.00%)	2 / 22 (9.09%)	0 / 16 (0.00%)	1 / 21 (4.76%)	2 / 15 (13.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0	0 / 1	0 / 2
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 / 36 (0.00%)	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (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
Acute respiratory failure
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Lung infiltration
subjects affected / exposed	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (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
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (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
Device related infection
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Pneumonia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (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
Upper respiratory tract infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	1 / 21 (4.76%)	0 / 15 (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
Septic shock
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Influenza
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Pneumonia influenzal
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Gastroenteritis
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Product issues
Device malfunction
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (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
Device extrusion
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (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
Device breakage
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	1 / 21 (4.76%)	0 / 15 (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

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

Non-serious adverse events	Rodatristat Ethyl 300 mg BID	Placebo	Rodatristat Ethyl 600 mg BID	Rodatristat Ethyl 300 mg-Rodatristat Ethyl 600 mg	Rodatristat Ethyl 300 mg-Rodatristat Ethyl 300 mg	Placebo-Rodatristat Ethyl 600 mg	Rodatristat Ethyl 600 mg-Rodatristat Ethyl 600 mg	Placebo-Rodatristat Ethyl 300 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 36 (88.89%)	27 / 36 (75.00%)	34 / 36 (94.44%)	2 / 2 (100.00%)	12 / 22 (54.55%)	15 / 16 (93.75%)	17 / 21 (80.95%)	12 / 15 (80.00%)
Vascular disorders
Hypotension
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	2 / 22 (9.09%)	0 / 16 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0
Essential hypertension
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 36 (0.00%)	2 / 36 (5.56%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	4	1	0	0	0	0	0
Asthenia
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	2	0	1	0	1	0	1	0
Pyrexia
subjects affected / exposed	3 / 36 (8.33%)	1 / 36 (2.78%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	6	1	3	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	4 / 36 (11.11%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	6	0	1	0	0	1	0	0
Non-cardiac chest pain
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	4	0	1	0	0	0	1	0
Fatigue
subjects affected / exposed	5 / 36 (13.89%)	3 / 36 (8.33%)	2 / 36 (5.56%)	0 / 2 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	5	4	3	0	1	1	0	0
Pain
subjects affected / exposed	3 / 36 (8.33%)	2 / 36 (5.56%)	1 / 36 (2.78%)	0 / 2 (0.00%)	2 / 22 (9.09%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	3	2	2	0	2	0	0	0
Adverse drug reaction
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0
Peripheral swelling
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	0	0	0	0	1	0	1
Device related thrombosis
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 2 (50.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0
Lithiasis
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Reproductive system and breast disorders
Prostatomegaly
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 2 (50.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 36 (2.78%)	4 / 36 (11.11%)	4 / 36 (11.11%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	3 / 21 (14.29%)	2 / 15 (13.33%)
occurrences all number	1	4	4	0	0	0	3	2
Dysphonia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	1 / 36 (2.78%)	3 / 36 (8.33%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	3	0	0	1	0	0	1
Nasal congestion
subjects affected / exposed	1 / 36 (2.78%)	2 / 36 (5.56%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	1 / 21 (4.76%)	1 / 15 (6.67%)
occurrences all number	1	2	0	0	1	0	1	1
Productive cough
subjects affected / exposed	1 / 36 (2.78%)	2 / 36 (5.56%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	2	0	0	0	0	0	0
Bronchospasm
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Pulmonary arterial hypertension
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	2 / 36 (5.56%)	0 / 2 (0.00%)	2 / 22 (9.09%)	1 / 16 (6.25%)	1 / 21 (4.76%)	1 / 15 (6.67%)
occurrences all number	1	0	2	0	2	1	1	2
Epistaxis
subjects affected / exposed	1 / 36 (2.78%)	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	1	0	0	0	0	0	1
Hiccups
subjects affected / exposed	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	0	0	0	0	0	1
Sinus congestion
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Dyspnoea
subjects affected / exposed	5 / 36 (13.89%)	4 / 36 (11.11%)	2 / 36 (5.56%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	2 / 21 (9.52%)	1 / 15 (6.67%)
occurrences all number	6	6	2	0	1	0	2	1
Upper-airway cough syndrome
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 36 (0.00%)	3 / 36 (8.33%)	4 / 36 (11.11%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	0	3	4	0	0	0	1	0
Anxiety
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	3 / 36 (8.33%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	3 / 21 (14.29%)	0 / 15 (0.00%)
occurrences all number	0	0	3	0	0	0	4	0
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	3 / 36 (8.33%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	5	0	0	0	1	0	0	0
Anticoagulation drug level below therapeutic
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	1	0	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	4 / 36 (11.11%)	0 / 36 (0.00%)	3 / 36 (8.33%)	0 / 2 (0.00%)	2 / 22 (9.09%)	2 / 16 (12.50%)	1 / 21 (4.76%)	1 / 15 (6.67%)
occurrences all number	4	0	4	0	2	2	1	1
Aspartate aminotransferase increased
subjects affected / exposed	5 / 36 (13.89%)	0 / 36 (0.00%)	4 / 36 (11.11%)	0 / 2 (0.00%)	2 / 22 (9.09%)	1 / 16 (6.25%)	1 / 21 (4.76%)	1 / 15 (6.67%)
occurrences all number	6	0	5	0	2	1	1	1
Gamma-glutamyltransferase increased
subjects affected / exposed	14 / 36 (38.89%)	0 / 36 (0.00%)	11 / 36 (30.56%)	0 / 2 (0.00%)	3 / 22 (13.64%)	7 / 16 (43.75%)	3 / 21 (14.29%)	4 / 15 (26.67%)
occurrences all number	26	0	20	0	7	18	6	10
Platelet count decreased
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	2	0	0	0	0	0	1	0
White blood cell count decreased
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	1	2	0
Weight decreased
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
SARS-CoV-2 test positive
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Pancreatic enzymes increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 2 (50.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Blood pH increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Blood potassium decreased
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 2 (50.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Hepatic enzyme increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 36 (0.00%)	3 / 36 (8.33%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	3	1	0	0	0	0	0
Cardiac disorders
Extrasystoles
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Pericardial effusion
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 2 (50.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Supraventricular tachycardia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	2
Sinus tachycardia
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	2 / 22 (9.09%)	0 / 16 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	3	0	0	0	2	0	1	0
Palpitations
subjects affected / exposed	1 / 36 (2.78%)	5 / 36 (13.89%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	5	0	0	1	0	0	0
Right ventricular failure
subjects affected / exposed	2 / 36 (5.56%)	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	2 / 16 (12.50%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	2	1	0	0	0	2	0	1
Ventricular extrasystoles
subjects affected / exposed	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	0	0	0	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	3 / 36 (8.33%)	2 / 36 (5.56%)	3 / 36 (8.33%)	1 / 2 (50.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)	3 / 21 (14.29%)	1 / 15 (6.67%)
occurrences all number	4	2	4	1	1	1	3	1
Syncope
subjects affected / exposed	3 / 36 (8.33%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	2 / 21 (9.52%)	1 / 15 (6.67%)
occurrences all number	4	0	0	0	0	0	2	1
Dizziness
subjects affected / exposed	3 / 36 (8.33%)	5 / 36 (13.89%)	3 / 36 (8.33%)	1 / 2 (50.00%)	2 / 22 (9.09%)	1 / 16 (6.25%)	0 / 21 (0.00%)	2 / 15 (13.33%)
occurrences all number	3	5	3	2	2	1	0	2
Ageusia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Somnolence
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	1 / 21 (4.76%)	1 / 15 (6.67%)
occurrences all number	0	0	1	0	0	0	1	1
Hypotonia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Anosmia
subjects affected / exposed	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 36 (0.00%)	1 / 2 (50.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	0	1	0	1	1	1	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 36 (5.56%)	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	3	1	0	0	0	1	0	0
Thrombocytopenia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 2 (50.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 36 (2.78%)	1 / 36 (2.78%)	1 / 36 (2.78%)	0 / 2 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	1	1	1	0	1	1	1	0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	4 / 36 (11.11%)	0 / 36 (0.00%)	8 / 36 (22.22%)	0 / 2 (0.00%)	2 / 22 (9.09%)	5 / 16 (31.25%)	5 / 21 (23.81%)	2 / 15 (13.33%)
occurrences all number	5	0	9	0	3	7	5	3
Diarrhoea
subjects affected / exposed	9 / 36 (25.00%)	4 / 36 (11.11%)	17 / 36 (47.22%)	0 / 2 (0.00%)	1 / 22 (4.55%)	6 / 16 (37.50%)	3 / 21 (14.29%)	2 / 15 (13.33%)
occurrences all number	11	5	24	0	2	11	4	3
Nausea
subjects affected / exposed	11 / 36 (30.56%)	3 / 36 (8.33%)	13 / 36 (36.11%)	1 / 2 (50.00%)	4 / 22 (18.18%)	3 / 16 (18.75%)	2 / 21 (9.52%)	3 / 15 (20.00%)
occurrences all number	14	4	17	1	4	3	2	3
Abdominal distension
subjects affected / exposed	3 / 36 (8.33%)	0 / 36 (0.00%)	4 / 36 (11.11%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	3	0	5	0	0	1	0	0
Abdominal pain
subjects affected / exposed	2 / 36 (5.56%)	1 / 36 (2.78%)	4 / 36 (11.11%)	0 / 2 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	2	1	4	0	1	1	1	0
Dyspepsia
subjects affected / exposed	2 / 36 (5.56%)	1 / 36 (2.78%)	2 / 36 (5.56%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	1	2	0	0	1	0	0
Abdominal pain lower
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	0	0	0	0	0	0	1
Gastrointestinal sounds abnormal
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Pancreatitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 2 (50.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Constipation
subjects affected / exposed	2 / 36 (5.56%)	3 / 36 (8.33%)	1 / 36 (2.78%)	1 / 2 (50.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	1 / 21 (4.76%)	1 / 15 (6.67%)
occurrences all number	2	3	1	2	1	0	1	1
Flatulence
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	0	0	0	1	0	0	1
Eructation
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1	0	0	1
Toothache
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	2 / 21 (9.52%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1	0	2	1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 36 (2.78%)	1 / 36 (2.78%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	3 / 16 (18.75%)	1 / 21 (4.76%)	1 / 15 (6.67%)
occurrences all number	1	1	1	0	0	3	1	1
Abdominal pain upper
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	2 / 36 (5.56%)	0 / 2 (0.00%)	0 / 22 (0.00%)	2 / 16 (12.50%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	0	0	5	0	0	2	1	0
Abdominal discomfort
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	2 / 36 (5.56%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Hepatobiliary disorders
Congestive hepatopathy
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 36 (5.56%)	2 / 36 (5.56%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	3	3	0	0	0	0	0	0
Renal and urinary disorders
Ureterolithiasis
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 2 (50.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Nocturia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Hydronephrosis
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 2 (50.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 36 (2.78%)	1 / 36 (2.78%)	2 / 36 (5.56%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	1	1	2	0	1	0	1	0
Pain in extremity
subjects affected / exposed	1 / 36 (2.78%)	1 / 36 (2.78%)	2 / 36 (5.56%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	1	2	0	0	1	0	1
Myalgia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	2 / 21 (9.52%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	2	0	2	0
Infections and infestations
COVID-19
subjects affected / exposed	5 / 36 (13.89%)	8 / 36 (22.22%)	3 / 36 (8.33%)	1 / 2 (50.00%)	5 / 22 (22.73%)	7 / 16 (43.75%)	6 / 21 (28.57%)	3 / 15 (20.00%)
occurrences all number	5	8	3	1	5	8	6	5
Influenza
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	1	0	0	0	0	0
Respiratory tract infection
subjects affected / exposed	1 / 36 (2.78%)	2 / 36 (5.56%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	2 / 15 (13.33%)
occurrences all number	1	2	1	0	0	1	0	2
Nasopharyngitis
subjects affected / exposed	1 / 36 (2.78%)	3 / 36 (8.33%)	2 / 36 (5.56%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	4	2	0	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	1 / 21 (4.76%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	1	1	0
Urinary tract infection
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	1	1	0	0
Urinary tract infection bacterial
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 36 (0.00%)	2 / 36 (5.56%)	1 / 36 (2.78%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	2 / 21 (9.52%)	0 / 15 (0.00%)
occurrences all number	0	3	1	0	0	1	2	0
Pneumonia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	2 / 22 (9.09%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	2	1	0	0
Respiratory tract infection viral
subjects affected / exposed	3 / 36 (8.33%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	3	0	0	0	0	0	0	0
Abscess limb
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Bronchitis
subjects affected / exposed	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	0	0	0	0	0	1
Helicobacter infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Infusion site infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Vaginal infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 36 (8.33%)	1 / 36 (2.78%)	2 / 36 (5.56%)	0 / 2 (0.00%)	3 / 22 (13.64%)	1 / 16 (6.25%)	1 / 21 (4.76%)	1 / 15 (6.67%)
occurrences all number	3	1	2	0	3	1	1	1
Hypokalaemia
subjects affected / exposed	2 / 36 (5.56%)	3 / 36 (8.33%)	1 / 36 (2.78%)	0 / 2 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)	2 / 21 (9.52%)	1 / 15 (6.67%)
occurrences all number	3	3	1	0	1	1	2	1
Fluid retention
subjects affected / exposed	0 / 36 (0.00%)	2 / 36 (5.56%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Hypoglycaemia
subjects affected / exposed	2 / 36 (5.56%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	3	0	0	0	1	0	0	0
Fluid overload
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	2 / 22 (9.09%)	0 / 16 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	2	0	0	0
Hypertriglyceridaemia
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Glucose tolerance impaired
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Iron deficiency
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hyperkalaemia
subjects affected / exposed	1 / 36 (2.78%)	0 / 36 (0.00%)	1 / 36 (2.78%)	0 / 2 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	1	0	2	1	0	0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 36 (0.00%)	0 / 2 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)	0 / 21 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0

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Were there any global substantial amendments to the protocol? Yes

19 Nov 2020

• Country Site list updated, Netherlands deleted & Czech Republic, Lativa were added • Updated wording for Inclusion Criteria on age of patient who can be enrolled • Deleted Inclusion Criteria on male patient eligibility that has a female partner who is or intends to become pregnant • Deleted Exclusion Criteria for elevated liver enzymes • Added Objective & Endpoint to evaluate the effect of Study Drug on Selexipag • Updated wording on stratification & capping of patients on Slexipag • Updates to Schedule of Assessments 1. Physical Exam removed at Follow-Up Visit 2. Optional Sample for Future Research & Pharmacogenetic Sample was added 3. Updated Footnote to clarify when weight will be collected, when Study Drug should be taken on clinic visit days, when ECGs should be collected, & clarify Right Heart Catheterization eligibility 4. Updated Footnote to clarify collection of Pharmacokinetics & Pharmacodynamic samples 5 .Updated Footnote to remove wording on amount of Study Drug received on Open-Label Extension • Updated wording on description of Study Drug to reflect new tablet appearance • Updated wording on clarification of dosing & timing of Study Drug in Main Study and Open-Label Extension • Updated wording on who can unblind a patient and how to unblind • Updated wording to clarify when C-SSRS to be collected • Updated Concomitant Medications to include Covid-19 vaccine • Updated Appendix 1 list of Concomitant & Prohibited medications • Added scoring & formula for REVEAL Lite 2.0 risk calculator

21 Dec 2021

• Updated Protocol wording to reflect Synopsis wording • Additional countries added (Serbia, Republica of Moldova, Austria & Bosnia) and number of Sites updated to approximately 68 Sites • Clarified ex-US Sites are not under US IND • Updated wording for Inclusion Criteria number 3, 5, 6 & 7 • Updated wording for Exclusion Criteria number 4, 15 & 26 • Added Exclusion Criteria number 27, 28 & 29 • Updates to Schedule of Assessments 1. Pulmonary Function Test added at Screening Visit and Pharmacogenetic sample collection added to Week 24 visit 2. Echocardiogram assessment moved from Day 1Visit to Screening Visit 3. Dispensing study drug removed from Week 8 and Week 18 Visit, Plasma NT-proBNP level was removed from Screening Visit & REVEAL Lite 2.0 assessment was removed 4 .Updated when & how Pregnancy Test, Coagulation Test & Urine Creatinine will be obtained during study • Updated Appendix 1 list of Concomitant & Prohibited medications • Updated wording on how Pulmonary Arterial Hypertension-Symptoms & Impact Questionnaire will be administered • Updated wording on procedures to be taken if patient exhibits suicidal ideation or behavior while on Study Drug • Updated wording to define stopping criteria for Study Drug non-compliance & clarification of reporting of Adverse Events of Special Interest • Updated wording on when to use contraception during study & methods of effective birth control • Updated wording on what assessments may be repeated at Screening Visit • Wording added to clarify unblinding procedure & process for randomization in Open-Label Extension and define end of study for patient participation in study • Wording added to Background & Pharmacokinetics section • Total time patient with be on Study Drug in Open-Label Extension was added • Deleted section on Right Heart Catheterization parameters measured during study

19 Jan 2022

• Updates to Schedule of Assessments 1. Week 8 of Main Study and Open-Label Extension changed from telephone/telemed visit to clinic visit 2. Wording added to clarify Unscheduled Visits. Safety and Laboratory assessments may be conducted at any time during the study if Investigator or Sponsor deems it necessary for the safety of the patient • Updated Objectives and Endpoints 1. Peptide (NT-proBNP) was deleted from additional objectives since it was already under Secondary Endpoint

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
01 Jul 2023	terminated during the Open-Label Extension phase based on Interim-Analysis results.	-

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

None reported

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