Trial Outcomes & Findings for To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension. (NCT NCT00430716)

Last Updated: 2020-12-22

Results Overview

6 MWT was 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

TERMINATED

Study phase

PHASE4

Target enrollment

130 participants

Primary outcome timeframe

Baseline and Week 12

Results posted on

2020-12-22

Participant Flow

Participant milestones

Participant milestones
Measure	Sildenafil 1 mg Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Double Blind Phase STARTED	42	43	45
Double Blind Phase Treated	41	43	45
Double Blind Phase COMPLETED	36	38	39
Double Blind Phase NOT COMPLETED	6	5	6
Open Label Phase STARTED	36	38	39
Open Label Phase COMPLETED	27	31	32
Open Label Phase NOT COMPLETED	9	7	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Sildenafil 1 mg Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Double Blind Phase Death	1	0	0
Double Blind Phase No longer willing to participate	2	1	1
Double Blind Phase Other	0	2	0
Double Blind Phase Study terminated by sponsor	1	1	2
Double Blind Phase Adverse Event	1	1	3
Double Blind Phase Not treated	1	0	0
Open Label Phase Lost to Follow-up	1	0	1
Open Label Phase No longer willing to participate	0	1	1
Open Label Phase Other	3	1	1
Open Label Phase Protocol Violation	1	0	0
Open Label Phase Study terminated by sponsor	4	5	4

Baseline Characteristics

To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sildenafil 1 mg n=41 Participants Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=43 Participants Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=45 Participants Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).	Total n=129 Participants Total of all reporting groups
Age, Continuous	42.5 Years STANDARD_DEVIATION 16.5 • n=5 Participants	44.4 Years STANDARD_DEVIATION 17.4 • n=7 Participants	46.4 Years STANDARD_DEVIATION 17.7 • n=5 Participants	44.5 Years STANDARD_DEVIATION 17.2 • n=4 Participants
Sex: Female, Male Female	28 Participants n=5 Participants	33 Participants n=7 Participants	26 Participants n=5 Participants	87 Participants n=4 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants	42 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Week 12

Population: Intention to Treat (ITT population) included all participants who were randomized to study treatment and received at least 1 dose of study medication. If participant had missing value at any visit, last observation carried forward (LOCF) method of imputation was used.

Outcome measures

Outcome measures
Measure	Sildenafil 1 mg n=41 Participants Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=40 Participants Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=42 Participants Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 12	14.21 Meters Interval 0.41 to 28.0	40.75 Meters Interval 25.16 to 56.34	38.36 Meters Interval 23.77 to 52.94

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: ITT population included all participants who were randomized to study treatment and received at least 1 dose of study medication. If participant had missing value at any visit, LOCF method of imputation was used.

mPAP was measured using a pressure transducer positioned at the mid-axillary line.

Outcome measures

Outcome measures
Measure	Sildenafil 1 mg n=33 Participants Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=33 Participants Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=34 Participants Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) at Week 12	-1.73 mmHg Interval -5.99 to 2.54	-3.44 mmHg Interval -5.87 to -1.0	-3.29 mmHg Interval -6.05 to -0.52

SECONDARY outcome

Timeframe: Baseline through Week 12

Population: ITT population for clinical worsening included all participants who had been randomized to study treatment and received at least 1 dose of study medication.

Clinical worsening was defined as death; or lung transplantation; or hospitalization due to pulmonary hypertension; or initiation of prostacyclin therapy; or initiation of endothelin receptor antagonist therapy. (PAH=pulmonary arterial hypertension) Due to very low number of events of clinical worsening reported, the median days to clinical worsening could not be estimated.

Outcome measures

Outcome measures
Measure	Sildenafil 1 mg n=41 Participants Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=43 Participants Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=45 Participants Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Number of Participants With Clinical Worsening death	1 Participants	1 Participants	0 Participants
Number of Participants With Clinical Worsening lung transplantation	0 Participants	0 Participants	0 Participants
Number of Participants With Clinical Worsening hospitalisation due to pulmonary hypertension	1 Participants	0 Participants	2 Participants
Number of Participants With Clinical Worsening PAH deterioration requiring therapy	0 Participants	0 Participants	0 Participants
Number of Participants With Clinical Worsening receptor antagonist therapy	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline and Week 12

Pulmonary arterial hypertension (PAH) Criteria for WHO Class: Class I (Participants without resulting limitation of physical activity);Class II (Participants with slight limitation of physical activity though comfortable at rest);Class III (Participants with marked limitation of physical activity,though comfortable at rest);Class IV(Participants with inability to carry out any physical activity without symptoms,manifest signs of right heart failure; dyspnoea and/or fatigue may even be present at rest; and discomfort is increased by any physical activity).

Outcome measures

Outcome measures
Measure	Sildenafil 1 mg n=41 Participants Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=43 Participants Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=45 Participants Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Number of Participants With Change From Baseline in PAH Criteria for Functional Capacity and Therapeutic Class at Week 12 Worsened 2 Classes	0 Participants	0 Participants	0 Participants
Number of Participants With Change From Baseline in PAH Criteria for Functional Capacity and Therapeutic Class at Week 12 Worsened 1 Class	1 Participants	3 Participants	2 Participants
Number of Participants With Change From Baseline in PAH Criteria for Functional Capacity and Therapeutic Class at Week 12 No Change	35 Participants	27 Participants	35 Participants
Number of Participants With Change From Baseline in PAH Criteria for Functional Capacity and Therapeutic Class at Week 12 Improved 1 Class	4 Participants	10 Participants	6 Participants
Number of Participants With Change From Baseline in PAH Criteria for Functional Capacity and Therapeutic Class at Week 12 Improved 2 Classes	1 Participants	0 Participants	0 Participants
Number of Participants With Change From Baseline in PAH Criteria for Functional Capacity and Therapeutic Class at Week 12 Missing	0 Participants	3 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline and Week 12

BNP is a non-invasive biomarker and an indicator of progression of PAH/ right ventricular dysfunction in participants with PAH.

Outcome measures

Outcome measures
Measure	Sildenafil 1 mg n=38 Participants Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=39 Participants Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=42 Participants Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Change From Baseline in B-Type Natriuretic Peptide (BNP) at Week 12	-6.28 pg/mL Interval -80.75 to 68.19	-53.46 pg/mL Interval -99.98 to -6.94	-97.42 pg/mL Interval -161.45 to -33.39

SECONDARY outcome

Timeframe: Baseline and Week 12

Pro- BNP which is a precursor of BNP, is a non-invasive biomarker and an indicator of progression of PAH / RV dysfunction in participants with PAH.

Outcome measures

Outcome measures
Measure	Sildenafil 1 mg n=39 Participants Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=40 Participants Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=43 Participants Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Change From Baseline in Pro-BNP at Week 12	-111.53 pg/mL Interval -507.68 to 284.63	-306.76 pg/mL Interval -523.82 to -89.7	-428.54 pg/mL Interval -676.74 to -180.34

SECONDARY outcome

Timeframe: Baseline and Week 12

Tricuspid annular plane systolic excursion (TAPSE) was measured as the total displacement of the tricuspid annulus in cm from end diastole to end systole.TAPSE is an indicator of progression of PAH /right ventricular dysfunction. The baseline data for 33 participants were measured incorrectly and the results from the 33 participants (both baseline and post-baseline) were excluded from the analysis.

Outcome measures

Outcome measures
Measure	Sildenafil 1 mg n=32 Participants Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=29 Participants Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=28 Participants Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Change From Baseline in TAPSE Measurement at Week 12	0.08 cm Interval -0.04 to 0.19	0.17 cm Interval 0.05 to 0.29	-0.02 cm Interval -0.15 to 0.1

SECONDARY outcome

Timeframe: Baseline and Week 12

BORG dyspnoea scale is a 10-point scale where following scores stands for severity of dyspnoea: 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

Outcome measures
Measure	Sildenafil 1 mg n=41 Participants Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=40 Participants Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=42 Participants Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Change From Baseline in BORG Dyspnoea Score at Week 12	-0.28 Units on a scale Interval -0.76 to 0.2	-0.89 Units on a scale Interval -1.35 to -0.43	-0.43 Units on a scale Interval -0.94 to 0.08

Adverse Events

Sildenafil 1 mg

Serious events: 6 serious events

Other events: 21 other events

Deaths: 1 deaths

Sildenafil 5 mg

Serious events: 3 serious events

Other events: 22 other events

Deaths: 1 deaths

Sildenafil 20 mg

Serious events: 5 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

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

Serious adverse events
Measure	Sildenafil 1 mg n=41 participants at risk Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=43 participants at risk Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=45 participants at risk Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
Blood and lymphatic system disorders Anaemia	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Atrial flutter	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Cor pulmonale	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	4.4% 2/45 • 24 Weeks The same event may appear as both an AE and an 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 Gastrointestinal haemorrhage	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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.
Hepatobiliary disorders Hepatitis	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Drug hypersensitivity	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Lower respiratory tract infection	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Ankle fracture	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 fibrosis	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 infarction	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Gastrooesophageal reflux disease	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Blood electrolytes abnormal	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 International normalised ratio increased	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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	Sildenafil 1 mg n=41 participants at risk Sildenafil 1 milligram (mg) tablet taken orally 3 times a day (TID) for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 5 mg n=43 participants at risk Sildenafil 5 mg tablet taken orally TID for first 12 weeks (double blind treatment phase of the study) and placebo matched to 20 mg. For a further 12 weeks (open label extension phase), participants received sildenafil 20 mg tablets TID.	Sildenafil 20 mg n=45 participants at risk Sildenafil 20 mg tablet taken orally TID throughout the study and placebo matched to 1 and 5 mg during first 12 weeks (double blind treatment phase).
General disorders Fatigue	4.9% 2/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Feeling hot	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Medical device pain	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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.	4.4% 2/45 • 24 Weeks The same event may appear as both an AE and an 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 Pyrexia	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Subcutaneous abscess	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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.	4.4% 2/45 • 24 Weeks The same event may appear as both an AE and an 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 jaw	4.9% 2/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Dizziness	7.3% 3/41 • 24 Weeks The same event may appear as both an AE and an 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.	4.7% 2/43 • 24 Weeks The same event may appear as both an AE and an 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.	4.4% 2/45 • 24 Weeks The same event may appear as both an AE and an 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 Dysgeusia	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Conjunctivitis bacterial	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Gastroenteritis	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Herpes zoster	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Infected bites	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Influenza	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Lower respiratory tract infection	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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	4.9% 2/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Otitis externa	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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.	4.4% 2/45 • 24 Weeks The same event may appear as both an AE and an 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 Leukocytosis	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Lymphadenopathy	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Cyanosis	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Tachyarrhythmia	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Tachycardia	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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.
Congenital, familial and genetic disorders Hereditary haemorrhagic telangiectasia	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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.
Ear and labyrinth disorders Ear pain	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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.
Ear and labyrinth disorders Vertigo	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Conjunctivitis	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Periorbital oedema	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 Photophobia	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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 distension	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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% 0/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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.	4.7% 2/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Dyspepsia	2.4% 1/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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.	2.2% 1/45 • 24 Weeks The same event may appear as both an AE and an 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 Dysphagia	0.00% 0/41 • 24 Weeks The same event may appear as both an AE and an 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.	2.3% 1/43 • 24 Weeks The same event may appear as both an AE and an 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% 0/45 • 24 Weeks The same event may appear as both an AE and an 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.