Trial Outcomes & Findings for This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure (NCT NCT01035255)

Last Updated: 2016-08-15

Results Overview

Number of participants that had first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization due to HF.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

8442 participants

Primary outcome timeframe

up to 51 months

Results posted on

2016-08-15

Participant Flow

Participant milestones

Participant milestones
Measure	LCZ696 single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period	Enalapril single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period
Overall Study STARTED	4209	4233
Overall Study GCP Violations	18	19
Overall Study Mis-randomized	4	2
Overall Study Full Analysis Set (FAS)	4187	4212
Overall Study COMPLETED	3468	3371
Overall Study NOT COMPLETED	741	862

Reasons for withdrawal

Reasons for withdrawal
Measure	LCZ696 single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period	Enalapril single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period
Overall Study Death	724	844
Overall Study Lost to Follow-up	2	5
Overall Study patient's request	15	13

Baseline Characteristics

This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LCZ696 n=4209 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period	Enalapril n=4233 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period	Total n=8442 Participants Total of all reporting groups
Age, Continuous	63.78 years STANDARD_DEVIATION 11.520 • n=39 Participants	63.82 years STANDARD_DEVIATION 11.25 • n=41 Participants	63.80 years STANDARD_DEVIATION 11.385 • n=35 Participants
Sex: Female, Male Female	888 Participants n=39 Participants	959 Participants n=41 Participants	1847 Participants n=35 Participants
Sex: Female, Male Male	3321 Participants n=39 Participants	3274 Participants n=41 Participants	6595 Participants n=35 Participants

PRIMARY outcome

Timeframe: up to 51 months

Population: Full Analysis Set (FAS) included all randomized patients but the following two exclusions: 6 patients who did not qualify for randomization but were inadvertently randomized into the study and did not receive double-blind study medication; 37 patients because they were randomized at sites that were closed due to serious GCP violations

Number of participants that had first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization due to HF.

Outcome measures

Outcome measures
Measure	LCZ696 n=4187 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period	Enalapril n=4212 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period
Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization Primary Composite	914 participants	1117 participants
Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization CV death	558 participants	693 participants
Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization 1st HF Hospitalization	537 participants	658 participants

SECONDARY outcome

Timeframe: up to 51 months

Number of patients - All-cause mortality. All-cause mortality is common in Heart Failure HF patients this measures how many patients had this event. The data is on FAS population up to March 31, 2014

Outcome measures

Outcome measures
Measure	LCZ696 n=4187 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period	Enalapril n=4212 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period
Number of Patients - All-cause Mortality	711 participants	835 participants

SECONDARY outcome

Timeframe: up to 51 months

Population: Randomized set (RAN): Consisted of all patients who received a randomization number, regardless of receiving trial medication.

Number of patients reported with adjudicated primary causes of death. The data is on Randomization population up to March 31, 2014

Outcome measures

Outcome measures
Measure	LCZ696 n=4209 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period	Enalapril n=4233 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period
Number of Patients Reported With Adjudicated Primary Causes of Death CV Death - Pump Failure	147 participants	185 participants
Number of Patients Reported With Adjudicated Primary Causes of Death CV Death - Sudden Death	251 participants	311 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Number of patients who died	714 participants	837 participants
Number of Patients Reported With Adjudicated Primary Causes of Death CV Death - Fatal MI	25 participants	33 participants
Number of Patients Reported With Adjudicated Primary Causes of Death CV Death - Presumed Sudden Death	26 participants	23 participants
Number of Patients Reported With Adjudicated Primary Causes of Death CV Death - Presumed CV Death	67 participants	95 participants
Number of Patients Reported With Adjudicated Primary Causes of Death CV Death - Fatal Stroke	30 participants	34 participants
Number of Patients Reported With Adjudicated Primary Causes of Death CV Death - Pulmonary Embolism	4 participants	3 participants
Number of Patients Reported With Adjudicated Primary Causes of Death CV Death - CV procedural	3 participants	4 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Other CV Death	7 participants	6 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Non-CV death - Infection	36 participants	34 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Non-CV death - Malignancy	41 participants	41 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Non-CV death - Renal	1 participants	1 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Non-CV death - Accidental	13 participants	6 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Non-CV death - Pulmonary	7 participants	13 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Non-CV death - Suicide	4 participants	1 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Non-CV death - GI	16 participants	10 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Other Non-CV death	2 participants	4 participants
Number of Patients Reported With Adjudicated Primary Causes of Death Unknown Death	34 participants	33 participants

SECONDARY outcome

Timeframe: Baseline, Month 8

Population: FAS included all randomized patients with two exclusions: 6 pts who did not qualify for randomization but were misrandomized into the study and did not receive study meds; 37 pts because they were randomized at sites that were closed due to serious GCP violations The analysis included all FAS patients with at least one KCCQ data up-to Month 8.

Change from baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. KCCQ clinical summary score is a composite assessment of physical limitations and total symptom scores. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.

Outcome measures

Outcome measures
Measure	LCZ696 n=3833 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period	Enalapril n=3873 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period
Change From Baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score	-2.99 KCCQ Score Standard Error 0.364	-4.63 KCCQ Score Standard Error 0.364

SECONDARY outcome

Timeframe: up to 51 months

Number of patients with first confirmed renal dysfunction

Outcome measures

Outcome measures
Measure	LCZ696 n=4187 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period	Enalapril n=4212 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period
Number of Patients With First Confirmed Renal Dysfunction	94 participants	108 participants

SECONDARY outcome

Timeframe: up to 51 months

Population: The new onset atrial fibrillation (AF) analysis was based on a subset of FAS: i.e., for patients without a history of AF at baseline (patients with a history of AF were excluded from this analysis).

Percentage of participants with New Onset of Atrial Fibrillation The new onset atrial fibrillation (AF) analysis was based on a subset of FAS: i.e., for patients without a history of AF at baseline (patients with a history of AF were excluded from this analysis).

Outcome measures

Outcome measures
Measure	LCZ696 n=2670 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period	Enalapril n=2638 Participants single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period
Percentage of Participants With New Onset of Atrial Fibrillation (AF)	3.15 Percentage of participants	3.15 Percentage of participants

Adverse Events

LCZ696

Serious events: 1937 serious events

Other events: 2479 other events

Deaths: 0 deaths

Enalapril

Serious events: 2142 serious events

Other events: 2594 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER

Measure	LCZ696 n=4203 participants at risk single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period	Enalapril n=4229 participants at risk single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period
Blood and lymphatic system disorders Anaemia	3.3% 140/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	3.8% 160/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Cardiac disorders Angina pectoris	3.0% 125/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	3.0% 125/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Cardiac disorders Atrial fibrillation	3.8% 159/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	3.2% 137/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Cardiac disorders Cardiac failure	5.1% 214/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	6.5% 274/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Gastrointestinal disorders Constipation	2.0% 85/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.8% 120/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Gastrointestinal disorders Diarrhoea	4.2% 175/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	4.2% 179/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Gastrointestinal disorders Nausea	2.0% 82/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.3% 96/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
General disorders Fatigue	3.0% 124/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.9% 121/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
General disorders Non-cardiac chest pain	1.8% 77/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.2% 92/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
General disorders Oedema peripheral	4.9% 205/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	4.8% 201/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Infections and infestations Bronchitis	3.9% 166/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	4.8% 202/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Infections and infestations Influenza	3.7% 154/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	3.0% 128/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Infections and infestations Nasopharyngitis	4.9% 204/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	4.1% 174/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Infections and infestations Pneumonia	2.2% 91/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	1.7% 70/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Infections and infestations Upper respiratory tract infection	4.7% 199/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	4.5% 191/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Infections and infestations Urinary tract infection	3.9% 166/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	3.9% 167/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Metabolism and nutrition disorders Diabetes mellitus	2.4% 101/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.6% 112/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Metabolism and nutrition disorders Gout	2.8% 116/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.7% 114/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Metabolism and nutrition disorders Hyperkalaemia	11.3% 477/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	13.5% 569/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Metabolism and nutrition disorders Hyperuricaemia	2.6% 108/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	3.5% 149/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Metabolism and nutrition disorders Hypokalaemia	3.1% 130/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.3% 98/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Musculoskeletal and connective tissue disorders Arthralgia	3.0% 124/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.8% 117/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Musculoskeletal and connective tissue disorders Back pain	3.7% 157/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	3.3% 138/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Musculoskeletal and connective tissue disorders Pain in extremity	2.2% 91/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.3% 98/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Nervous system disorders Dizziness	6.2% 259/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	4.8% 202/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Nervous system disorders Headache	2.4% 100/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.5% 106/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Psychiatric disorders Insomnia	2.2% 92/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.2% 91/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Renal and urinary disorders Renal failure	1.7% 73/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	2.3% 97/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Renal and urinary disorders Renal impairment	9.4% 393/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	10.6% 449/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Respiratory, thoracic and mediastinal disorders Cough	8.7% 367/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	12.5% 528/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.1% 173/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	6.2% 263/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Vascular disorders Hypertension	2.7% 115/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	4.4% 185/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.
Vascular disorders Hypotension	16.7% 700/4203 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.	10.7% 454/4229 Safety Population (SAF): Consisted of all randomized patients who received at least one dose of study drug during double-blind period of the study. Patients were analyzed according to the treatment actually received.