Trial Outcomes & Findings for A Study of the Effectiveness of Sitaxsentan Sodium in Patients With Diastolic Heart Failure (NCT NCT00303498)

Last Updated: 2023-01-04

Results Overview

Treadmill exercise test is used to assess the functional capacity of participants with cardiac disease. Treadmill exercise test was conducted using the 2 minute incremental Naughton protocol. The Naughton protocol starts with a 2 minute warm-up. The speed of treadmill is set to 1 mile per hour (mph) and the incline is set to 0. After the warm-up, the speed is set at 2 mph for the remainder of the test. The test consists of six, 2 minute intervals. The grade starts at 0 for the first interval, and increases by 3.5 percent every 2 minutes. The change in total exercise time (in seconds) during the treadmill test was reported.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

200 participants

Primary outcome timeframe

Baseline, Week 24 (Maintenance Phase)

Results posted on

2023-01-04

Participant Flow

Study consisted of a 10-week dose adjusting Run-In Phase followed by a 24-week Maintenance Phase.

Participant milestones

Participant milestones
Measure	Sitaxsentan During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Run-In-Phase (10 Weeks) STARTED	128	64
Run-In-Phase (10 Weeks) Treated	127	64
Run-In-Phase (10 Weeks) COMPLETED	104	56
Run-In-Phase (10 Weeks) NOT COMPLETED	24	8
Maintenance Phase (24 Weeks) STARTED	104	56
Maintenance Phase (24 Weeks) COMPLETED	90	48
Maintenance Phase (24 Weeks) NOT COMPLETED	14	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Sitaxsentan During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Run-In-Phase (10 Weeks) Adverse Event	5	1
Run-In-Phase (10 Weeks) Physician Decision	0	1
Run-In-Phase (10 Weeks) Withdrawal by Subject	5	0
Run-In-Phase (10 Weeks) Sponsor Decision	6	3
Run-In-Phase (10 Weeks) Other	4	1
Run-In-Phase (10 Weeks) Treatment Interrupted More Than 7 Days	3	2
Run-In-Phase (10 Weeks) Unable to Tolerate 25 mg Dose	1	0
Maintenance Phase (24 Weeks) Elevation in Liver Enzyme Values	1	0
Maintenance Phase (24 Weeks) Death	1	0
Maintenance Phase (24 Weeks) Adverse Event	2	1
Maintenance Phase (24 Weeks) Physician Decision	1	0
Maintenance Phase (24 Weeks) Withdrawal by Subject	3	4
Maintenance Phase (24 Weeks) Sponsor Decision	4	0
Maintenance Phase (24 Weeks) Other	1	0
Maintenance Phase (24 Weeks) Treatment Interrupted More Than 7 Days	1	2
Maintenance Phase (24 Weeks) Required Chronic Heart Failure Treatment	0	1

Baseline Characteristics

A Study of the Effectiveness of Sitaxsentan Sodium in Patients With Diastolic Heart Failure

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sitaxsentan n=127 Participants During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo n=64 Participants Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).	Total n=191 Participants Total of all reporting groups
Age, Continuous	65.0 Years STANDARD_DEVIATION 10.94 • n=5 Participants	64.7 Years STANDARD_DEVIATION 9.99 • n=7 Participants	64.9 Years STANDARD_DEVIATION 10.61 • n=5 Participants
Sex: Female, Male Female	76 Participants n=5 Participants	45 Participants n=7 Participants	121 Participants n=5 Participants
Sex: Female, Male Male	51 Participants n=5 Participants	19 Participants n=7 Participants	70 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 24 (Maintenance Phase)

Population: Intent-to-treat (ITT) population was defined as all participants who received at least 1 dose of study drug and had at least 1 valid treadmill test value at baseline and post-baseline during maintenance phase. Last observation carried forward (LOCF) method was used to impute missing values.

Outcome measures

Outcome measures
Measure	Sitaxsentan n=96 Participants During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo n=52 Participants Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Change From Baseline in Treadmill Exercise Time at Maintenance Phase Week 24 Baseline	424.5 Seconds Interval 121.0 to 706.0	485.0 Seconds Interval 126.0 to 693.0
Change From Baseline in Treadmill Exercise Time at Maintenance Phase Week 24 Change at Week 24	89.5 Seconds Interval -235.0 to 549.0	37.0 Seconds Interval -141.0 to 490.0

SECONDARY outcome

Timeframe: Baseline, Week 24 (Maintenance Phase)

Population: ITT population was defined as all the participants who received at least 1 dose of study drug and had at least 1 valid treadmill test value at baseline and post-baseline during maintenance phase. Here, "Overall Number of Participants Analyzed" signifies number of participants who were evaluable for this outcome measure and 'Number Analyzed' signifies the participants who were evaluable at the specified time points for each group, respectively.

Ratio of E to E' is used as a predictor of first cardiac events. Ratio of E to E' was measured using imaging techniques based on Doppler principles. Transmitral inflow velocity was measured by Doppler echocardiography (ECHO) and the early diastolic velocity of the mitral annulus was measured by tissue Doppler imaging (TDI).

Outcome measures

Outcome measures
Measure	Sitaxsentan n=73 Participants During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo n=49 Participants Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Change From Baseline in Ratio of Transmitral Inflow Velocity (E) to Early Diastolic Velocity of the Mitral Annulus (E') at Maintenance Phase Week 24 Baseline	13.72 Ratio Standard Deviation 6.975	14.45 Ratio Standard Deviation 6.565
Change From Baseline in Ratio of Transmitral Inflow Velocity (E) to Early Diastolic Velocity of the Mitral Annulus (E') at Maintenance Phase Week 24 Change at Week 24	-0.12 Ratio Standard Deviation 4.404	0.38 Ratio Standard Deviation 4.498

SECONDARY outcome

Timeframe: Baseline, Week 24 (Maintenance Phase)

Population: ITT population defined as all participants who received at least 1 dose of study drug and had at least 1 valid treadmill test value at baseline and post-baseline during maintenance phase. Here, "Overall Number of Participants Analyzed" signifies number of participants who were evaluable for this outcome measure and 'Number Analyzed' signifies the participants who were evaluable at the specified time points for each group, respectively.

Left ventricular mass was used as a parameter for the assessment of cardiac function. An increase in left ventricular mass leads to ventricular hypertrophy which is a prognostic factor of cardiovascular morbidity and mortality. Left ventricular mass was measured by ECHO, which was calculated as (1.04 \* \[{left ventricular end diastolic diameter (LVEDD) + septal diastolic thickness + post wall diastolic thickness}\^3 - LVEDD\^3\]) \* 0.8 + 0.6. Left ventricular mass was assessed for the two ECHO modes: parasternal long-axis two dimensional (PLAX 2D) mode and parasternal short-axis view motion (PSAX M) mode.

Outcome measures

Outcome measures
Measure	Sitaxsentan n=55 Participants During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo n=31 Participants Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Change From Baseline in Left Ventricular Mass at Maintenance Phase Week 24 Baseline: PLAX 2D mode	217.73 Centimeter^3 Standard Deviation 80.467	226.14 Centimeter^3 Standard Deviation 83.415
Change From Baseline in Left Ventricular Mass at Maintenance Phase Week 24 Baseline: PSAX M-mod	229.88 Centimeter^3 Standard Deviation 70.251	229.19 Centimeter^3 Standard Deviation 108.891
Change From Baseline in Left Ventricular Mass at Maintenance Phase Week 24 Change at Week 24: PLAX 2D mode	3.09 Centimeter^3 Standard Deviation 43.647	-7.52 Centimeter^3 Standard Deviation 42.582
Change From Baseline in Left Ventricular Mass at Maintenance Phase Week 24 Change at Week 24: PSAX M-mode	5.60 Centimeter^3 Standard Deviation 45.641	4.83 Centimeter^3 Standard Deviation 10.565

SECONDARY outcome

Timeframe: Baseline, Week 24 (Maintenance Phase)

Population: ITT population. Here, "Overall Number of Participants Analyzed" signifies number of participants who were evaluable for this outcome measure. LOCF method was used to impute missing values.

The MLHF is a 21-item questionnaire which used to evaluate QoL in participants suffering from heart failure. The participants were asked to evaluate how their heart condition affected their life during the past month. Each of the 21 items were assessed on a 6-point scale, where 0 = no affect and 5 = very much affected. The MLHF QoL total score was calculated as the sum of the 21 individual QoL questions. The MLHF QoL total score ranged from 0 to 105, where higher scores indicated worse health condition.

Outcome measures

Outcome measures
Measure	Sitaxsentan n=91 Participants During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo n=51 Participants Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Change From Baseline in Minnesota Living With Heart Failure (MLHF) Questionnaire - Quality of Life (QoL) Total Score at Maintenance Phase Week 24 Baseline	43.79 Units on a scale Standard Deviation 26.100	37.67 Units on a scale Standard Deviation 23.559
Change From Baseline in Minnesota Living With Heart Failure (MLHF) Questionnaire - Quality of Life (QoL) Total Score at Maintenance Phase Week 24 Change at Week 24	-8.20 Units on a scale Standard Deviation 21.493	-6.31 Units on a scale Standard Deviation 18.909

SECONDARY outcome

Timeframe: Baseline, Week 24 (Maintenance Phase)

The MLHF is a 21-item questionnaire which is used to evaluate QoL in participants suffering from heart failure. The participants were asked to evaluate how their heart condition affected their life during the past month. Each of the 21 items were assessed on a 6-point scale, where 0 = no affect and 5 = very much affected. The MLHF QoL physical score was calculated as the sum of the 8 physical domain QoL questions. The MLHF QoL physical score ranged from 0 to 40, where higher scores indicated worse health condition.

Outcome measures

Outcome measures
Measure	Sitaxsentan n=94 Participants During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo n=52 Participants Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Change From Baseline in Minnesota Living With Heart Failure (MLHF) Questionnaire - Quality of Life (QoL) Physical Score at Maintenance Phase Week 24 Baseline	21.73 Units on a scale Standard Deviation 11.740	18.85 Units on a scale Standard Deviation 10.151
Change From Baseline in Minnesota Living With Heart Failure (MLHF) Questionnaire - Quality of Life (QoL) Physical Score at Maintenance Phase Week 24 Change at Week 24	-4.06 Units on a scale Standard Deviation 10.365	-2.35 Units on a scale Standard Deviation 8.753

SECONDARY outcome

Timeframe: Baseline, Week M24 (Maintenance Phase)

The MLHF is a 21-item questionnaire which is used to evaluate QoL in participants suffering from heart failure. The participants were asked to evaluate how their heart condition affected their life during the past month. Each of the 21 items were assessed on a 6-point scale, where 0 = no affect and 5 = very much affected. The MLHF QoL emotional score was calculated as the sum of the 5 emotional domain QoL questions. The MLHF QoL emotional score ranged from 0 to 25, where higher scores indicated worse health condition.

Outcome measures

Outcome measures
Measure	Sitaxsentan n=93 Participants During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo n=52 Participants Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Change From Baseline in Minnesota Living With Heart Failure (MLHF) Questionnaire - Quality of Life (QoL) Emotional Score at Maintenance Phase Week 24 Baseline	8.97 Units on a scale Standard Deviation 7.562	7.37 Units on a scale Standard Deviation 6.914
Change From Baseline in Minnesota Living With Heart Failure (MLHF) Questionnaire - Quality of Life (QoL) Emotional Score at Maintenance Phase Week 24 Change at Week 24	-1.87 Units on a scale Standard Deviation 6.094	-1.40 Units on a scale Standard Deviation 5.815

SECONDARY outcome

Timeframe: Baseline, Week 24 (Maintenance Phase)

Population: ITT population. LOCF method was used to impute missing values.

Participants were classified by NYHA functional class. NYHA class I: participants with cardiac disease but without resulting limitations of physical activity, NYHA class II: participants with cardiac disease resulting in slight limitation of physical activity, NYHA class III: participants with cardiac disease resulting in marked limitation of physical activity, NYHA class IV: participants with cardiac disease resulting in inability to carry on any physical activity without discomfort. Baseline was reported by NYHA functional class and the change from baseline in the functional class was reported as improvement (positive change from baseline), no change and deterioration (negative change from baseline).

Outcome measures

Outcome measures
Measure	Sitaxsentan n=96 Participants During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo n=52 Participants Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Number of Participants With Change From Baseline in New York Heart Association (NYHA) Functional Class at Maintenance Phase Week 24 Baseline: Class II	58 Participants	27 Participants
Number of Participants With Change From Baseline in New York Heart Association (NYHA) Functional Class at Maintenance Phase Week 24 Baseline: Class III	38 Participants	25 Participants
Number of Participants With Change From Baseline in New York Heart Association (NYHA) Functional Class at Maintenance Phase Week 24 Improvement	30 Participants	18 Participants
Number of Participants With Change From Baseline in New York Heart Association (NYHA) Functional Class at Maintenance Phase Week 24 No change	60 Participants	34 Participants
Number of Participants With Change From Baseline in New York Heart Association (NYHA) Functional Class at Maintenance Phase Week 24 Deterioration	6 Participants	0 Participants

Adverse Events

Sitaxsentan

Serious events: 25 serious events

Other events: 107 other events

Deaths: 0 deaths

Placebo

Serious events: 16 serious events

Other events: 54 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	Sitaxsentan n=127 participants at risk During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo n=64 participants at risk Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Infections and infestations Upper respiratory tract infection	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Angina unstable	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Arrhythmia supraventricular	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Atrioventricular block second degree	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 congestive	1.6% 2/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.1% 2/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	2.4% 3/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Diastolic dysfunction	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Myocardial infarction	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Duodenitis	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Hiatus hernia	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Large intestine perforation	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Peptic ulcer haemorrhage	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	2.4% 3/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.1% 2/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Generalised oedema	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Multi-organ failure	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Non-cardiac chest pain	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.1% 2/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Diverticulitis	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Incision site infection	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 3/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	1.6% 2/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Intervertebral disc protrusion	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Osteoarthritis	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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) Hepatic cancer	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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) Lymphoma	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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) Non-small cell lung cancer	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Cerebrovascular accident	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Transient ischaemic attack	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Confusional state	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Acute kidney injury	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Bladder disorder	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Chronic kidney disease	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	Sitaxsentan n=127 participants at risk During the Run-In Phase, participants received sitaxsentan 25 milligram (mg) dose orally once daily for 2 weeks (Week 1 and Week 2). The dose was then up-titrated to 50 mg for the next 2 weeks (Week 3 and Week 4), and then to 75 mg for following 2 weeks (Week 5 and Week 6). The dose was finally up-titrated to the target study dose of 100 mg for the next 2 weeks (Week 7 and Week 8), with an additional 2-week stabilization period (up to Week 10). If a participant was unable to tolerate the upward dose titration to the target dose of 100 mg, the participant continued at the last titrated dose for the remainder of the Run-In Phase. During the Maintenance Phase, participants continued to receive the target dose of 100 mg or the maximum up-titrated Run-In Phase dose for 24 weeks.	Placebo n=64 participants at risk Participants received placebo matched to sitaxsentan orally once daily for 34 weeks (10-Week Run-In Phase and 24-Week Maintenance Phase).
Blood and lymphatic system disorders Anaemia	5.5% 7/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Eosinophilia	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Angina pectoris	2.4% 3/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 3/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 fibrillation	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Atrioventricular block second degree	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Bundle branch block right	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	1.6% 2/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 congestive	1.6% 2/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 flutter	1.6% 2/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Low cardiac output syndrome	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	4.7% 6/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	12.5% 8/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Pulmonary valve disease	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Supraventricular extrasystoles	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Supraventricular tachycardia	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	1.6% 2/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Endocrine disorders Thyroid cyst	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Blindness transient	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Eye allergy	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Eye haemorrhage	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Eye irritation	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Glaucoma	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Lacrimation increased	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Posterior capsule rupture	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.1% 2/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 discomfort	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	1.6% 2/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 hernia	2.4% 3/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	2.4% 3/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 upper	2.4% 3/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Constipation	1.6% 2/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.8% 5/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Dental caries	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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	4.7% 6/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.1% 2/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Dry mouth	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Duodenal ulcer	0.00% 0/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 3/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.2% 4/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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 Flatulence	0.79% 1/127 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious 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% 0/64 The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.