Trial Outcomes & Findings for Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes. (NCT NCT02887183)

NCT ID: NCT02887183

Last Updated: 2021-10-07

Results Overview

Change in concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to one year

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 794 participants
• Primary outcome timeframe: Baseline, one year
• Results posted on: 2021-10-07

Participant Flow

Of 1031 patients screened for the study, 795 completed screening and were enrolled. One (1) patient completed screening but withdrew consent and did not enter the treatment phase. Therefore, the Full Analysis Set and the Safety Set was based on 794 patients.

Participant milestones

Measure	LCZ696(Sacubitril/Valsartan) Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Overall Study STARTED	795
Overall Study Full Analysis Set	794
Overall Study COMPLETED	654
Overall Study NOT COMPLETED	141

Reasons for withdrawal

Measure	LCZ696(Sacubitril/Valsartan) Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Overall Study Adverse Event	44
Overall Study Death	30
Overall Study Pregnancy	1
Overall Study Protocol Violation	6
Overall Study Technical Problems	2
Overall Study Lost to Follow-up	13
Overall Study Physician Decision	10
Overall Study Withdrawal by Subject	35

Baseline Characteristics

Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes.

Baseline characteristics by cohort

Measure	LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	369 Participants n=5 Participants
Age, Categorical >=65 years	425 Participants n=5 Participants
Sex: Female, Male Female	226 Participants n=5 Participants
Sex: Female, Male Male	568 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	6 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	180 Participants n=5 Participants
Race (NIH/OMB) White	581 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	27 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, one year

Population: Full Analysis Set

Change in concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to one year

Outcome measures

Measure

LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.

Change in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to One Year

0.5905 pg/mL Interval 0.547 to 0.6375

PRIMARY outcome

Timeframe: Baseline, one Year

Population: Full Analysis Set

Change in left atrial volume index (LAVi), left ventricular end diastolic volume index (LVEDVi), left ventricular end systolic volume index (LVESVi), and from baseline to one year

Outcome measures

Measure	LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Change in Left Atrial Volume Index (LAVi), Left Ventricular End Diastolic Volume Index (LVEDVi), Left Ventricular End Systolic Volume Index (LVESVi), and From Baseline to One Year LAVi	-7.57 mL/m^2 Standard Deviation 6.06
Change in Left Atrial Volume Index (LAVi), Left Ventricular End Diastolic Volume Index (LVEDVi), Left Ventricular End Systolic Volume Index (LVESVi), and From Baseline to One Year LVESVi	-15.35 mL/m^2 Standard Deviation 9.61
Change in Left Atrial Volume Index (LAVi), Left Ventricular End Diastolic Volume Index (LVEDVi), Left Ventricular End Systolic Volume Index (LVESVi), and From Baseline to One Year LVEDVi	-12.33 mL/m^2 Standard Deviation 8.89

PRIMARY outcome

Timeframe: Baseline, one year

Population: Full Analysis Set

Change in Left ventricular ejection fraction (LVEF) from baseline to one year. LVEF is a measurement expressed as a percentage of how much blood the left ventricle pumps out with each contraction.

Outcome measures

Measure

LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.

Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to One Year

9.38 Percentage Standard Deviation 6.85

PRIMARY outcome

Timeframe: Baseline, one year

Population: Full Analysis Set

Pearson's correlation coefficient was calculated between change in log-transformed NT-proBNP and change in structural cardiac measurements LVESVi, LVEDVi, LAVi, and LVEF from baseline to one year.

Outcome measures

Measure	LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Change in Log-transformed NT-proBNP and Change in Structural Cardiac Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to One Year LVESVi	0.405 Pearson's Correlation Interval 0.335 to 0.47
Change in Log-transformed NT-proBNP and Change in Structural Cardiac Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to One Year LVEDVi	0.320 Pearson's Correlation Interval 0.246 to 0.391
Change in Log-transformed NT-proBNP and Change in Structural Cardiac Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to One Year LAVi	0.263 Pearson's Correlation Interval 0.186 to 0.338
Change in Log-transformed NT-proBNP and Change in Structural Cardiac Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to One Year LVEF	-0.381 Pearson's Correlation Interval -0.448 to -0.31

SECONDARY outcome

Timeframe: Baseline, Month 6

Population: Full Analysis Set

Pearson's correlation coefficient was calculated between change in log-transformed NT-proBNP and change in echocardiographic measurements LVESVi, LVEDVi, LAVi, and LVEF from baseline to Month 6

Outcome measures

Measure	LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Change in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6 LVESVi	0.233 Pearson's Correlation Interval 0.159 to 0.305
Change in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6 LVEDVi	0.164 Pearson's Correlation Interval 0.088 to 0.238
Change in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6 LAVi	0.190 Pearson's Correlation Interval 0.113 to 0.264
Change in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6 LVEF	-0.226 Pearson's Correlation Interval -0.298 to -0.152

SECONDARY outcome

Timeframe: Baseline, Month 6

Population: Full Analysis Set

Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LAVi from baseline to 6 months overall in subgroups of interest, these subgroups are:

1. Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline.

2. Subjects with new onset HF and/or RAAS naïve.

3. Subjects who are not receiving the target sacubitril/valsartan dose.

Outcome measures

Measure	LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Change in Left Atrial Volume Index (LAVi) by Selected Groups of Interest at Month 6 Subjects with new onset HF and/or RAAS naïve	0.487 Pearson's Correlation Coefficient Interval 0.311 to 0.631
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Change in Left Atrial Volume Index (LAVi) by Selected Groups of Interest at Month 6 Subjects with HFrEF and "low" NT-proBNP	0.228 Pearson's Correlation Coefficient Interval 0.105 to 0.345
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Change in Left Atrial Volume Index (LAVi) by Selected Groups of Interest at Month 6 Subjects not receiving target dose	0.117 Pearson's Correlation Coefficient Interval -0.021 to 0.251

SECONDARY outcome

Timeframe: Baseline, Month 6

Population: Full Analysis Set

Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVESVi from baseline to 6 months overall in subgroups of interest, these subgroups are:

1. Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline.

2. Subjects with new onset HF and/or RAAS naïve.

3. Subjects who are not receiving the target sacubitril/valsartan dose.

Outcome measures

Measure	LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Systolic Volume Index (LVESVi) by Selected Groups of Interest at Month 6 Subjects with new onset HF and/or RAAS naïve	0.285 Pearson's Correlation Coefficient Interval 0.083 to 0.465
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Systolic Volume Index (LVESVi) by Selected Groups of Interest at Month 6 Subjects with HFrEF and "low" NT-proBNP	0.201 Pearson's Correlation Coefficient Interval 0.08 to 0.316
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Systolic Volume Index (LVESVi) by Selected Groups of Interest at Month 6 Subjects not receiving target dose	0.165 Pearson's Correlation Coefficient Interval 0.028 to 0.295

SECONDARY outcome

Timeframe: Baseline, Month 6

Population: Full Analysis Set

Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVEDVi from baseline to 6 months overall in subgroups of interest, these subgroups are:

1. Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline.

2. Subjects with new onset HF and/or RAAS naïve.

3. Subjects who are not receiving the target sacubitril/valsartan dose.

Outcome measures

Measure	LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Diastolic Volume Index (LVEDVi) by Selected Groups of Interest at Month 6 Subjects with new onset HF and/or RAAS naïve	0.122 Pearson's Correlation Coefficient Interval -0.087 to 0.321
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Diastolic Volume Index (LVEDVi) by Selected Groups of Interest at Month 6 Subjects with HFrEF and "low" NT-proBNP	0.123 Pearson's Correlation Coefficient Interval 0.0 to 0.243
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Diastolic Volume Index (LVEDVi) by Selected Groups of Interest at Month 6 Subjects not receiving target dose	0.078 Pearson's Correlation Coefficient Interval -0.06 to 0.213

SECONDARY outcome

Timeframe: Baseline, Month 6

Population: Full Analysis Set

Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVEF from baseline to 6 months overall in subgroups of interest, these subgroups are:

1. Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline.

2. Subjects with new onset HF and/or RAAS naïve.

3. Subjects who are not receiving the target sacubitril/valsartan dose.

Outcome measures

Measure	LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular Ejection Fraction (LVEF) by Selected Groups of Interest at Month 6 Subjects with new onset HF and/or RAAS naïve	-0.308 Pearson's Correlation Coefficient Interval -0.484 to -0.107
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular Ejection Fraction (LVEF) by Selected Groups of Interest at Month 6 Subjects with HFrEF and "low" NT-proBNP	-0.202 Pearson's Correlation Coefficient Interval -0.317 to -0.081
Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular Ejection Fraction (LVEF) by Selected Groups of Interest at Month 6 Subjects not receiving target dose	-0.224 Pearson's Correlation Coefficient Interval -0.351 to -0.09

SECONDARY outcome

Timeframe: Baseline, month 12

Population: Full Analysis Set

The KCCQ-23 is a self-administered questionnaire and requires, on average, 4-6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). A change of 5 points on the scale scores, either as a group mean difference or an intra-individual change appears to be clinically significant, based on comparisons of changes in the scale scores to clinical indicators and subject global reports of change. The analysis will be done for groups of subjects with N-terminal pro-brain natriuretic peptide<1000 pg/mL and N-Terminal pro-brain natriuretic peptide>=1000 pg/mL at Month 12.

Outcome measures

Measure

LCZ696(Sacubitril/Valsartan) n=794 Participants Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.

Mean Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score From Baseline to Month 12

10.39 Points on a scale Standard Deviation 19.39

Adverse Events

LCZ696 (Sacubitril/Valsartan)

Serious events: 240 serious events

Other events: 384 other events

Deaths: 30 deaths

Serious adverse events

Measure	LCZ696 (Sacubitril/Valsartan) n=794 participants at risk Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily
Nervous system disorders Lumbosacral radiculopathy	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Blood and lymphatic system disorders Anaemia	0.63% 5/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Blood and lymphatic system disorders Coagulopathy	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Blood and lymphatic system disorders Iron deficiency anaemia	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Blood and lymphatic system disorders Leukocytosis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Acute left ventricular failure	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Acute myocardial infarction	0.88% 7/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Angina pectoris	1.0% 8/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Atrial fibrillation	1.0% 8/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Atrial flutter	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Atrial thrombosis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Atrioventricular block complete	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Atrioventricular block second degree	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Bradycardia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Cardiac arrest	0.50% 4/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Cardiac failure	1.8% 14/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Cardiac failure acute	0.76% 6/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Cardiac failure congestive	7.6% 60/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Cardiac perforation	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Cardiac ventricular thrombosis	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Cardiogenic shock	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Cardiomyopathy	0.76% 6/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Cardiorenal syndrome	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Ischaemic cardiomyopathy	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Left ventricular failure	1.8% 14/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Mitral valve incompetence	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Myocardial infarction	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Myocardial ischaemia	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Pericardial effusion	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Pericarditis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Sinus tachycardia	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Supraventricular tachycardia	0.63% 5/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Ventricular arrhythmia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Ventricular extrasystoles	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Ventricular fibrillation	1.0% 8/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Cardiac disorders Ventricular tachycardia	1.5% 12/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Ear and labyrinth disorders Vertigo	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Abdominal pain	0.63% 5/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Ascites	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Colitis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Constipation	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Diarrhoea	0.63% 5/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Dysphagia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Enteritis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Gastritis	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.63% 5/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Gastrointestinal necrosis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Ileus	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Incarcerated umbilical hernia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Inguinal hernia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Intestinal pseudo-obstruction	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Melaena	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Nausea	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Pancreatitis	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Peptic ulcer	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Retroperitoneal mass	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Small intestinal obstruction	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Spigelian hernia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Gastrointestinal disorders Vomiting	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Asthenia	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Chest pain	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Death	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Fatigue	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Hernia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Medical device site haematoma	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Multiple organ dysfunction syndrome	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Non-cardiac chest pain	1.6% 13/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Oedema peripheral	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Pain	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Peripheral swelling	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Physical deconditioning	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Pyrexia	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Systemic inflammatory response syndrome	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Hepatobiliary disorders Hepatic cirrhosis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Hepatobiliary disorders Hepatic steatosis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Hepatobiliary disorders Hepatitis toxic	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Abscess oral	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Arthritis bacterial	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Atypical pneumonia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Bacterial sepsis	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Bronchitis	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Bronchitis viral	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Cellulitis	0.50% 4/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Clostridium difficile colitis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Corona virus infection	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Device related infection	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Diverticulitis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Gastroenteritis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Gastroenteritis viral	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Hepatitis C	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Influenza	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Localised infection	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Osteomyelitis	0.76% 6/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Periorbital cellulitis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Pneumonia	2.5% 20/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Pneumonia bacterial	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Pneumonia viral	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Pyelonephritis	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Respiratory syncytial virus infection	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Respiratory tract infection viral	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Sepsis	0.88% 7/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Septic shock	0.50% 4/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Staphylococcal infection	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Staphylococcal sepsis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Streptococcal infection	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Streptococcal sepsis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Upper respiratory tract infection	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Urinary tract infection	0.88% 7/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Vascular device infection	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Alcohol poisoning	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Ankle fracture	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Brain herniation	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Cervical vertebral fracture	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Clavicle fracture	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Extradural haematoma	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Fall	0.63% 5/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Femoral neck fracture	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Femur fracture	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Head injury	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Limb injury	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Rib fracture	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Injury, poisoning and procedural complications Subdural haemorrhage	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Investigations Alanine aminotransferase increased	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Investigations Liver function test increased	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Dehydration	0.63% 5/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Diabetes mellitus	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Electrolyte imbalance	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Failure to thrive	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Fluid overload	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Fluid retention	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Gout	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Hyperammonaemia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Hyperglycaemia	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Hyperkalaemia	1.1% 9/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Hypoglycaemia	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Hypokalaemia	0.76% 6/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Hypomagnesaemia	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Hyponatraemia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Hypophosphataemia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Malnutrition	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Arthralgia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Back pain	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Fasciitis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Flank pain	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Gouty arthritis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Muscular weakness	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Neck pain	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Pain in extremity	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Spondylitis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Musculoskeletal and connective tissue disorders Vertebral osteophyte	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder transitional cell carcinoma stage II	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bone cancer metastatic	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung cancer metastatic	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung carcinoma cell type unspecified stage IV	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic carcinoma	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Plasma cell myeloma	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell carcinoma	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Ataxia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Carotid artery disease	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Cerebral infarction	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Cerebrovascular accident	0.50% 4/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Dizziness	0.50% 4/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Embolic cerebral infarction	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Encephalopathy	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Haemorrhage intracranial	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Ischaemic cerebral infarction	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Ischaemic stroke	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Lethargy	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Metabolic encephalopathy	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Presyncope	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Seizure	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Syncope	1.4% 11/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Transient ischaemic attack	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Product Issues Device failure	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Product Issues Device malfunction	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Psychiatric disorders Alcohol withdrawal syndrome	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Psychiatric disorders Bipolar disorder	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Psychiatric disorders Depression	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Psychiatric disorders Drug abuse	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Psychiatric disorders Mental status changes	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Renal and urinary disorders Acute kidney injury	2.9% 23/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Renal and urinary disorders Chronic kidney disease	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Renal and urinary disorders End stage renal disease	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Renal and urinary disorders Haematuria	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Renal and urinary disorders Nephrolithiasis	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Renal and urinary disorders Renal failure	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Renal and urinary disorders Renal injury	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Renal and urinary disorders Urinary incontinence	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Renal and urinary disorders Urinary retention	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Reproductive system and breast disorders Ovarian cyst	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	1.3% 10/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Asthma	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.1% 9/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Chronic respiratory failure	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Cough	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.76% 6/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Emphysema	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Hypercapnia	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.50% 4/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Laryngospasm	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Pneumothorax spontaneous	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary alveolar haemorrhage	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.25% 2/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.3% 10/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Skin and subcutaneous tissue disorders Angioedema	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Skin and subcutaneous tissue disorders Dermatitis contact	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Skin and subcutaneous tissue disorders Diabetic foot	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Skin and subcutaneous tissue disorders Skin ulcer	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Skin and subcutaneous tissue disorders Stasis dermatitis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Surgical and medical procedures Resuscitation	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Aortic aneurysm	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Aortic stenosis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Circulatory collapse	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Deep vein thrombosis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Haematoma	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Hypertensive crisis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Hypotension	1.4% 11/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Hypovolaemic shock	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Labile blood pressure	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Orthostatic hypotension	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Pelvic venous thrombosis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Peripheral artery stenosis	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Peripheral ischaemia	0.38% 3/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Peripheral venous disease	0.13% 1/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.

Other adverse events

Measure	LCZ696 (Sacubitril/Valsartan) n=794 participants at risk Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily
Gastrointestinal disorders Diarrhoea	5.4% 43/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Fatigue	7.1% 56/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
General disorders Oedema peripheral	5.5% 44/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Infections and infestations Upper respiratory tract infection	7.3% 58/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Investigations Blood creatinine increased	5.2% 41/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Metabolism and nutrition disorders Hyperkalaemia	9.4% 75/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Nervous system disorders Dizziness	16.2% 129/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.8% 46/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Vascular disorders Hypotension	16.6% 132/794 • Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 12 months Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: Novartis.email@novartis.com

Results disclosure agreements

• Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
• Publication restrictions are in place

Restriction type: OTHER