Trial Outcomes & Findings for Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension (NCT NCT00323297)

NCT ID: NCT00323297

Last Updated: 2021-02-01

Results Overview

6MWT is the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 105 participants
• Primary outcome timeframe: Week 12
• Results posted on: 2021-02-01

Participant Flow

This study was conducted at 29 active centers in 10 countries (10 centers in Germany, 5 centers in the United States of America [USA], 3 centers in France, 2 centers in Australia, Czech Republic, Italy, and Israel, and 1 center in Greece, Taiwan and United Kingdom [UK])

Participants were on bosentan therapy for 3 months prior. Participants were randomized to sildenafil or placebo. Part A study was double-blind phase (12 weeks) and Part B was 12 months open-label phase. 53 and 51 participants were randomized to placebo and sildenafil arm respectively. One participant in sildenafil arm did not receive any treatment

Participant milestones

Measure	Placebo In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.	Sildenafil In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Part A (Double Blind Randomized) STARTED	53	50
Part A (Double Blind Randomized) COMPLETED	48	43
Part A (Double Blind Randomized) NOT COMPLETED	5	7
Part B (Open-label) STARTED	48	43
Part B (Open-label) COMPLETED	39	31
Part B (Open-label) NOT COMPLETED	9	12

Reasons for withdrawal

Measure	Placebo In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.	Sildenafil In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Part A (Double Blind Randomized) Reason unspecified	0	1
Part A (Double Blind Randomized) Death	0	1
Part A (Double Blind Randomized) Protocol Violation	1	3
Part A (Double Blind Randomized) Unrelated adverse event	1	0
Part A (Double Blind Randomized) Related and Unrelated adverse event	1	0
Part A (Double Blind Randomized) Related adverse event	2	2
Part B (Open-label) Death	0	1
Part B (Open-label) Reason unspecified	0	1
Part B (Open-label) Withdrawal by Subject	1	3
Part B (Open-label) Lack of Efficacy	3	1
Part B (Open-label) Adverse Event	5	5
Part B (Open-label) Protocol Violation	0	1

Baseline Characteristics

Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension

Baseline characteristics by cohort

Measure	Placebo n=53 Participants In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	Sildenafil n=50 Participants In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.	Total n=103 Participants Total of all reporting groups
Age, Continuous	56.9 Years STANDARD_DEVIATION 14.14 • n=93 Participants	55.2 Years STANDARD_DEVIATION 15.10 • n=4 Participants	56.0 Years STANDARD_DEVIATION 14.57 • n=27 Participants
Sex: Female, Male Female	41 Participants n=93 Participants	37 Participants n=4 Participants	78 Participants n=27 Participants
Sex: Female, Male Male	12 Participants n=93 Participants	13 Participants n=4 Participants	25 Participants n=27 Participants
Six Minute Walk Test (6MWT)	350.38 Meters STANDARD_DEVIATION 87.587 • n=93 Participants	354.44 Meters STANDARD_DEVIATION 73.121 • n=4 Participants	352.35 Meters STANDARD_DEVIATION 80.520 • n=27 Participants
Mean Pulmonary Artery Pressure (mPAP)	44.9 Millimeter(mm) of mercury(Hg) STANDARD_DEVIATION 13.33 • n=93 Participants	46.9 Millimeter(mm) of mercury(Hg) STANDARD_DEVIATION 12.47 • n=4 Participants	45.8 Millimeter(mm) of mercury(Hg) STANDARD_DEVIATION 12.89 • n=27 Participants
World Health Organization Functional Class in Participants with Pulmonary Arterial Hypertension Class I	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
World Health Organization Functional Class in Participants with Pulmonary Arterial Hypertension Class II	15 Participants n=93 Participants	20 Participants n=4 Participants	35 Participants n=27 Participants
World Health Organization Functional Class in Participants with Pulmonary Arterial Hypertension Class III	38 Participants n=93 Participants	29 Participants n=4 Participants	67 Participants n=27 Participants
World Health Organization Functional Class in Participants with Pulmonary Arterial Hypertension Class IV	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants

PRIMARY outcome

Timeframe: Week 12

Population: Intent-to-Treat (ITT) Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward (LOCF) approach. Statistical analysis was carried out on LOCF values.

6MWT is the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety.

Outcome measures

Measure	Placebo n=53 Participants In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	Sildenafil n=50 Participants In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12 Change from baseline at Week 12 LOCF (n=53,49)	14.08 Meters Standard Deviation 57.557	13.62 Meters Standard Deviation 60.950
Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12 Change from baseline at Week 12 (n=46,44)	17.42 Meters Standard Deviation 57.270	14.08 Meters Standard Deviation 63.679

SECONDARY outcome

Timeframe: Week 12

Population: ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the LOCF approach.

WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (can not perform a physical activity without any symptoms, dyspnea at rest). Improvement=reduction in functional class; deterioration = increase in functional class, no change = no change in functional class.

Outcome measures

Measure	Placebo n=53 Participants In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	Sildenafil n=50 Participants In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF Worsened 2 Classes	0 Participants	0 Participants
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF Worsened 1 Class	1 Participants	0 Participants
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF No Change	45 Participants	39 Participants
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF Improved 1 Class	7 Participants	10 Participants
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF Improved 2 Classes	0 Participants	0 Participants
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF Discontinued	0 Participants	0 Participants
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF Died	0 Participants	1 Participants
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF Missing	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Week 12

Population: ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication.

No survival analysis was carried out for the study due to very few events of clinical worsening. Hence, we present a summary of clinical worsening events instead.

Events of clinical worsening were categorized as (A). Death, (B). Heart/lung transplantation, (C). Hospitalization due to pulmonary arterial hypertension (PAH), and (D). Clinical deterioration of PAH requiring additional therapy.

Outcome measures

Measure	Placebo n=53 Participants In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	Sildenafil n=50 Participants In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Clinical Worsening Events None	51 Participants	47 Participants
Clinical Worsening Events (A)	0 Participants	1 Participants
Clinical Worsening Events (B)	0 Participants	0 Participants
Clinical Worsening Events (C)	2 Participants	2 Participants
Clinical Worsening Events (D)	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Week 12

Population: ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach.

Borg dyspnea scale is a 10-point scale where following scores stands for severity of dyspnea: 0 (no breathlessness at all); 0.5 (very very slight [just noticeable]);

1. (very slight);

2. (slight breathlessness);

3. (moderate); 4 (some what severe);

5 (severe breathlessness); 7 (very severe breathlessness); 9 (very very severe [almost maximum]); and 10 (maximum).

Outcome measures

Measure	Placebo n=53 Participants In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	Sildenafil n=50 Participants In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Change From Baseline in Borg Dyspnea Score at Week 12 Change from Baseline at Week 12 (n=46,43)	0.16 Units on a scale Standard Deviation 1.637	-0.73 Units on a scale Standard Deviation 1.656
Change From Baseline in Borg Dyspnea Score at Week 12 Change from Baseline at Week 12 LOCF (n=53,49)	0.24 Units on a scale Standard Deviation 1.709	-0.62 Units on a scale Standard Deviation 1.583

SECONDARY outcome

Timeframe: One year from the time of starting sildenafil

Population: ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach. The participants in placebo arm have received Sildenafil on or after Week 12.

The survival probability of all participants up to 1-year post start of Sildenafil treatment; for participants who were randomized to Sildenafil, this was the week 52 from randomization, and for participants who were originally randomized to Placebo group, this was the Week 64 from Baseline (Week 52 from Week 12, when the first dose of Sildenafil was administered to these participants). Those participants who discontinued from the study prior to 1 year after start of sildenafil were considered as censored at the time of discontinuation and those who discontinued from the study post 1-year after start of sildenafil were considered as censored at the time of 1-year post start of sildenafil.

Outcome measures

Measure	Placebo n=48 Participants In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	Sildenafil n=50 Participants In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
One Year Survival Probability From the Start of Sildenafil Treatment.	0.042 Probability of death Interval 0.013 to 0.127	0.040 Probability of death Interval 0.013 to 0.124

SECONDARY outcome

Timeframe: One year from the time of starting sildenafil

Population: ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach. The participants in placebo arm have received Sildenafil on or after Week 12.

The survival status of all participants who discontinued from the study, including those participants who discontinued during the double-blind phase, was to be assessed at one year post their Week 12 visit/ End of treatment visit.

Outcome measures

Measure	Placebo n=48 Participants In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months	Sildenafil n=50 Participants In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
One Year Survival From the Start of Sildenafil Treatment.	2 Participants who died	2 Participants who died

Adverse Events

Placebo

Serious events: 23 serious events

Other events: 38 other events

Deaths: 0 deaths

Sildenafil

Serious events: 22 serious events

Other events: 33 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=53 participants at risk In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.	Sildenafil n=50 participants at risk In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Blood and lymphatic system disorders Anaemia	3.8% 2/53 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Acute coronary syndrome	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Right ventricular failure	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.0% 3/50 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain	3.8% 2/53 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Inguinal hernia	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Asthenia	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Death	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Immune system disorders Contrast media allergy	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Bronchopneumonia	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.0% 2/50 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Erysipelas	3.8% 2/53 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Gastritis viral	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Haemoglobin decreased	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Osteoporosis	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Paresis	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.8% 2/53 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.0% 2/50 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pleural effusion	3.8% 2/53 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pulmonary arterial hypertension	11.3% 6/53 • Number of events 6 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.0% 2/50 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Circulatory collapse	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Hypertension	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiac failure	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiovascular disorder	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Coronary artery disease	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Mitral valve incompetence	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Pericardial effusion	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Chest discomfort	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders General physical health deterioration	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Oedema peripheral	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Abscess	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Gangrene	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Osteomyelitis	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Pneumonia	3.8% 2/53 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Respiratory syncytial virus infection	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Respiratory tract infection	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Sepsis	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Urinary tract infection	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Post procedural haematoma	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Walking distance test abnormal	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Fluid overload	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Fluid retention	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Back pain	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Pain in extremity	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic neoplasm	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Sciatica	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Syncope	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Mania	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Reproductive system and breast disorders Uterine haemorrhage	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Skin ulcer	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Surgical and medical procedures Skin graft	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.

Other adverse events

Measure	Placebo n=53 participants at risk In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.	Sildenafil n=50 participants at risk In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study. In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months.
Ear and labyrinth disorders Vertigo	3.8% 2/53 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	10.0% 5/50 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Vision blurred	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.0% 3/50 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	9.4% 5/53 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	14.0% 7/50 • Number of events 7 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	9.4% 5/53 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Oedema peripheral	15.1% 8/53 • Number of events 8 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	14.0% 7/50 • Number of events 7 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Bronchitis	9.4% 5/53 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	10.0% 5/50 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Nasopharyngitis	15.1% 8/53 • Number of events 8 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	10.0% 5/50 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Upper respiratory tract infection	9.4% 5/53 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.0% 2/50 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Back pain	9.4% 5/53 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Headache	13.2% 7/53 • Number of events 7 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	14.0% 7/50 • Number of events 7 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pulmonary arterial hypertension	7.5% 4/53 • Number of events 4 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.0% 2/50 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Flushing	7.5% 4/53 • Number of events 4 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	10.0% 5/50 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Anaemia	7.5% 4/53 • Number of events 4 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.0% 2/50 • Number of events 2 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Palpitations	5.7% 3/53 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	10.0% 5/50 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Right ventricular failure	7.5% 4/53 • Number of events 4 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Chest pain	7.5% 4/53 • Number of events 4 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Respiratory tract infection	1.9% 1/53 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	8.0% 4/50 • Number of events 4 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Sinusitis	9.4% 5/53 • Number of events 5 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Weight increased	5.7% 3/53 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Gout	5.7% 3/53 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	7.5% 4/53 • Number of events 4 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	5.7% 3/53 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Presyncope	5.7% 3/53 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.0% 3/50 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Syncope	5.7% 3/53 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/50 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Depression	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.0% 3/50 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Cough	5.7% 3/53 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dyspnoea	15.1% 8/53 • Number of events 8 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.0% 3/50 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/53 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.0% 3/50 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Hypertension	5.7% 3/53 • Number of events 3 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 1/50 • Number of events 1 • From the time that the participant provides informed consent through and including 28 calendar days after the last administration of the investigational product The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: ClinicalTrials.gov_Inquiries@pfizer.com

Results disclosure agreements

• Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
• Publication restrictions are in place

Restriction type: OTHER