Trial Outcomes & Findings for Impact Of Eplerenone On Cardiovascular Outcomes In Patients Post Myocardial Infarction (NCT NCT01176968)

Last Updated: 2020-12-22

Results Overview

Cardiovascular mortality is defined as any mortality adjudicated as death due to sudden cardiac death, myocardial infarction (MI), worsening heart failure, cardiac arrhythmia, other cause (such as pulmonary embolism, peripheral arterial disease \[PAD\], etc.). Hospitalization due to congestive heart failure (CHF) and requires extended hospital stay or frequent visits to emergency room, observation unit or in-patient care, due to CHF as the primary or secondary diagnosis supported by a discharge report or clinical summary for hospitalization as determined by the endpoint adjudication committee (EAC). A composite of time to first event of cardiovascular mortality (CV), re-hospitalization or extended initial hospital stay due to diagnosis of heart failure, sustained ventricular tachycardia or fibrillation, ejection fraction ≤40% after 1 month or BNP \>200 pg/mL or NT-proBNP \>450 pg/mL (age \<50 years); \>900 pg/mL (age 50 to 75 years) or \>1800 pg/mL (age \>75 years) after 1 month.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

1012 participants

Primary outcome timeframe

0-24 months

Results posted on

2020-12-22

Participant Flow

A total of 1012 subjects were enrolled for participation in this study. A total of 505 subjects were randomized to treatment with eplerenone and 505 subjects were randomized to the placebo group; a total of 422 and 424 subjects in the eplerenone and placebo groups, respectively, completed the study.

Participant milestones

Participant milestones
Measure	Eplerenone Plus Standard of Care Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Overall Study STARTED	506	506
Overall Study Treated	505	505
Overall Study COMPLETED	422	424
Overall Study NOT COMPLETED	84	82

Reasons for withdrawal

Reasons for withdrawal
Measure	Eplerenone Plus Standard of Care Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Overall Study Adverse Event	10	11
Overall Study Death	2	3
Overall Study Lack of Efficacy	0	1
Overall Study Lost to Follow-up	16	14
Overall Study Withdrawal by Subject	48	48
Overall Study Protocol Violation	2	1
Overall Study Did Not Meet Entrance Criteria	1	0
Overall Study Study terminated by sponsor	0	1
Overall Study Reason not defined	5	3

Baseline Characteristics

Impact Of Eplerenone On Cardiovascular Outcomes In Patients Post Myocardial Infarction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Eplerenone Plus Standard of Care n=506 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.	Total n=1012 Participants Total of all reporting groups
Age, Continuous	58.5 Years STANDARD_DEVIATION 10.8 • n=93 Participants	57.8 Years STANDARD_DEVIATION 11.0 • n=4 Participants	58.2 Years STANDARD_DEVIATION 10.9 • n=27 Participants
Sex: Female, Male Female	86 Participants n=93 Participants	103 Participants n=4 Participants	189 Participants n=27 Participants
Sex: Female, Male Male	420 Participants n=93 Participants	403 Participants n=4 Participants	823 Participants n=27 Participants

PRIMARY outcome

Timeframe: 0-24 months

Population: The Full Analysis Set (FAS) using the intent-to-treat (ITT) principle, regardless of compliance with the study drug and the protocol was used. The efficacy analysis data sets for clinical events included all available study endpoints.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=506 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
First Event of Cardiovascular Mortality, Re-hospitalization or Extended Initial Hospital Stay Due to Diagnosis of Heart Failure, Sustained Ventricular Tachycardia or Fibrillation, Ejection Fraction ≤40% or BNP Above Age Adjusted Cut Off	92 Events	149 Events

SECONDARY outcome

Timeframe: 0-24 months

Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used. The efficacy analysis data sets for clinical events included all available study endpoints. Furthermore, only events confirmed by the EAC were used.

The occurrence of cardiovascular mortality from randomization. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=506 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Cardiovascular Mortality	2 Events	2 Events

SECONDARY outcome

Timeframe: 0-24 months

The occurrence of first diagnosis of heart failure from the date of randomization. Time-to-event analyses were measured from the date of randomization, and a subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=506 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Diagnosis of Heart Failure	7 Events	11 Events

SECONDARY outcome

Timeframe: 0-24 months

The occurrence of first and each subsequent episode (after an event-free interval of ≥ 48 hours) of sustained ventricular tachycardia or ventricular fibrillation. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=506 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
First and Each Subsequent Episode (After an Event Free Interval of ≥ 48 Hours) of Sustained Ventricular Tachycardia or Ventricular Fibrillation.	0 Events	0 Events

SECONDARY outcome

Timeframe: 0-24 months

The occurrence of first recorded EF ≤40% (recorded 28 days or later post-randomization). Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=506 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
First Recorded Ejection Fraction (EF) of ≤40% (Recorded 1 Month or Later Post-randomization).	20 Events	19 Events

SECONDARY outcome

Timeframe: 0-24 months

Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.

The occurrence of first occurrence of BNP \>200 pg/mL or NT-proBNP \>450, \>900 or \>1800 pg/mL for ages \<50 years, 50 to 75 years and \>75 years, respectively (recorded 28 days or later post-randomization). Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=506 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Brain (B-type) Natriuretic Peptide (BNP) >200 pg/mL or NT-proBNP >450, >900 or >1800 pg/mL for Ages <50 Years, 50-75 Years and >75 Years, Respectively (Recorded 1 Month or Later Post-randomization).	81 Events	131 Events

SECONDARY outcome

Timeframe: 0-24 months

Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.

The decision to provide an ICD or CRT. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=506 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Decision to Provide an Implantable Cardioverter Defibrillator (ICD) or Cardiac Resynchronization Therapy (CRT).	3 Events	3 Events

SECONDARY outcome

Timeframe: 0-24 months

The occurrence of second or subsequent nonfatal MI. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=506 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Second or Subsequent Non-fatal Myocardial Infarction (MI).	10 Events	6 Events

SECONDARY outcome

Timeframe: 6 months

Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.

Electrocardiogram Q wave to the end of the S wave corresponding to ventricle depolarization (QRS) duration at 6 months post-randomization. The continuous endpoints were assessed using analysis of covariance (ANCOVA) model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on last observation carried forward (LOCF) and also using all available data up to end of study.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=347 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=343 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Electrocardiogram Q Wave to the End of the S Wave Corresponding to Ventricle Depolarization (QRS) Duration at 6 Months Post-randomization.	93.31 Milliseconds (msec) Standard Deviation 15.04	94.62 Milliseconds (msec) Standard Deviation 16.00

SECONDARY outcome

Timeframe: 0-24 months

Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.

LAD recorded each time an echocardiogram is conducted. The continuous endpoints were assessed using ANCOVA model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on LOCF and also using all available data up to end of study.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=506 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Left Atrial Diameter (LAD) (Recorded on Each Occasion an Echocardiogram is Conducted). Month 6 (N = 268, 243)	3.92 Centimeters (cm) Standard Deviation 0.654	3.90 Centimeters (cm) Standard Deviation 0.703
Left Atrial Diameter (LAD) (Recorded on Each Occasion an Echocardiogram is Conducted). Final Visit (N = 393, 378)	3.91 Centimeters (cm) Standard Deviation 0.641	3.87 Centimeters (cm) Standard Deviation 0.658

SECONDARY outcome

Timeframe: 6 months

Population: The Biomarker Analysis Set is a subset of FAS subjects who have the biomarker data (carboxyterminal telopeptide of type I collagen \[ICTP\], procollagen type I N-terminal peptide \[PINP\], procollagen type III N-terminal peptide \[PIIINP\], Interleukin-6, aldosterone, cortisol, and Galactin 3) available.

Change in serum levels of aldosterone and cortisol at 6 months post-randomization. The continuous endpoints were assessed using ANCOVA model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on LOCF and also using all available data up to end of study.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=266 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=260 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Change in Serum Levels of Biomarkers (Aldosterone and Cortisol) at 6 Months Post-randomization. Aldosterone	0.355 nmol/L Interval 0.21 to 0.54	0.210 nmol/L Interval 0.15 to 0.31
Change in Serum Levels of Biomarkers (Aldosterone and Cortisol) at 6 Months Post-randomization. Serum Cortisol	379.0 nmol/L Interval 292.0 to 492.0	366.0 nmol/L Interval 271.0 to 482.0

SECONDARY outcome

Timeframe: 6 months

Population: The Biomarker Analysis Set is a subset of FAS subjects who have the biomarker data (ICTP, PINP, PIIINP, Interleukin-6, aldosterone, cortisol, and Galactin 3) available.

Change in serum levels of PIIINP, Galectin 3, and PINP at 6 months post-randomization. The continuous endpoints were assessed using ANCOVA model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on LOCF and also using all available data up to end of study.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=266 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=260 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization. PIIINP	4.20 ng/mL Interval 3.5 to 4.9	4.30 ng/mL Interval 3.6 to 5.1
Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization. Galectin 3	11.20 ng/mL Interval 9.2 to 13.5	10.60 ng/mL Interval 9.1 to 12.4
Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization. PINP	30.0 ng/mL Interval 24.0 to 39.0	32.0 ng/mL Interval 24.0 to 42.0

SECONDARY outcome

Timeframe: 6 months

Population: The Biomarker Analysis Set is a subset of FAS subjects who have the biomarker data (ICTP, PINP, PIIINP, Interleukin-6, aldosterone, cortisol, and Galactin 3) available.

Change in serum level of ICTP at 6 months post-randomization. The continuous endpoint was assessed using ANCOVA model, fitted with corresponding baseline and treatment. It was analyzed at 6 months based on LOCF and also using all available data up to end of study.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=266 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=260 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Change in Serum Level of Biomarker (ICTP) at 6 Months Post-randomization.	3.70 μg/L Interval 3.2 to 4.5	3.70 μg/L Interval 3.2 to 4.8

SECONDARY outcome

Timeframe: 6 months

Population: The Biomarker Analysis Set is a subset of FAS subjects who have the biomarker data (ICTP, PINP, PIIINP, Interleukin-6, aldosterone, cortisol, and Galactin 3) available.

Change in serum level of Interleukin-6 at 6 months post-randomization. The continuous endpoint was assessed using ANCOVA model, fitted with corresponding baseline and treatment. It was analyzed at 6 months based on LOCF and also using all available data up to end of study.

Outcome measures

Outcome measures
Measure	Eplerenone Plus Standard of Care n=266 Participants Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=260 Participants Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Change in Serum Level of Biomarker (Interleukin-6) at 6 Months Post-randomization.	1.845 pg/mL Interval 1.235 to 2.955	1.755 pg/mL Interval 1.18 to 2.48

Adverse Events

Eplerenone Plus Standard of Care

Serious events: 100 serious events

Other events: 151 other events

Deaths: 0 deaths

Placebo Plus Standard of Care

Serious events: 101 serious events

Other events: 153 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

Measure	Eplerenone Plus Standard of Care n=506 participants at risk；n=505 participants at risk Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function.	Placebo Plus Standard of Care n=506 participants at risk；n=505 participants at risk Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Cardiac disorders Angina pectoris	3.2% 16/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.3% 22/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Bradycardia	2.4% 12/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.4% 7/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Ventricular tachycardia	2.2% 11/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.4% 7/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain upper	2.6% 13/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.59% 3/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Constipation	1.4% 7/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.6% 13/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	4.3% 22/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.8% 14/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	1.4% 7/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 11/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Chest pain	4.5% 23/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.7% 24/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Fatigue	2.0% 10/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.0% 20/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Non-cardiac chest pain	3.2% 16/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.6% 13/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Oedema peripheral	1.6% 8/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 11/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Diabetes mellitus	2.2% 11/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.2% 6/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Back pain	2.4% 12/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.6% 13/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Dizziness	4.2% 21/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.8% 19/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Headache	1.6% 8/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.2% 16/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Anxiety	2.2% 11/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.6% 8/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Cough	3.2% 16/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.4% 17/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.4% 12/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.4% 17/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Vascular disorders Hypertension	2.4% 12/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 18/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Vascular disorders Hypotension	4.2% 21/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.8% 19/506 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.