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    Clinical Trial Results:
    A 24-week, randomized, double-blind, multi-center, parallel group, active controlled study to evaluate the effect of LCZ696 on NT-proBNP, exercise capacity, symptoms and safety compared to individualized medical management of comorbidities in patients with heart failure and preserved ejection fraction

    Summary
    EudraCT number
    		 2016-003410-28
    Trial protocol
    		 PT   HU   LV   ES   FR   SK   CZ   GB   LT   AT   DK   BG   BE   NL   IT  
    Global end of trial date
    28 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Nov 2020
    First version publication date
    11 Nov 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLCZ696D2302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03066804
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The Primary Objectives were to demonstrate that sacubitril/valsartan is superior to individualized medical therapy for comorbidities in reducing N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline after 12 weeks of treatment, and to demonstrate that sacubitril/valsartan is superior to individualized medical therapy for comorbidities in improving exercise capacity as assessed by the six-minute walk test (6MWT) at Week 24 in a subset of patients
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 105
    Country: Number of subjects enrolled
    Austria: 31
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    Brazil: 77
    Country: Number of subjects enrolled
    Bulgaria: 178
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Colombia: 44
    Country: Number of subjects enrolled
    Czech Republic: 149
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Estonia: 51
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Germany: 417
    Country: Number of subjects enrolled
    Guatemala: 60
    Country: Number of subjects enrolled
    Hungary: 134
    Country: Number of subjects enrolled
    India: 97
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Italy: 48
    Country: Number of subjects enrolled
    Latvia: 18
    Country: Number of subjects enrolled
    Lithuania: 29
    Country: Number of subjects enrolled
    Mexico: 14
    Country: Number of subjects enrolled
    Netherlands: 52
    Country: Number of subjects enrolled
    Peru: 58
    Country: Number of subjects enrolled
    Portugal: 33
    Country: Number of subjects enrolled
    Romania: 93
    Country: Number of subjects enrolled
    Russian Federation: 139
    Country: Number of subjects enrolled
    Serbia: 26
    Country: Number of subjects enrolled
    Slovakia: 243
    Country: Number of subjects enrolled
    Spain: 127
    Country: Number of subjects enrolled
    Thailand: 12
    Country: Number of subjects enrolled
    Turkey: 74
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    United States: 119
    Worldwide total number of subjects
    2572
    EEA total number of subjects
    1703
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    418
    From 65 to 84 years
    2154
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 2572 participants were randomized in a 1:1 ratio to receive either sacubitril/valsartan or Individualized Medical Therapy (IMT).

    Pre-assignment
    Screening details
    		 A total of 2572 participants were randomized in a 1:1 ratio to receive either sacubitril/valsartan or Individualized Medical Therapy (IMT).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sacubitril/Valsartan (LCZ696)
    Arm description
    		 All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients in the ACEi strata received LCZ696 or enalapril. Patients in the ARB strata received LCZ696 or valsartan. Patients in the no RASi strata received LCZ696 or matching placebo. Patients in the ACEi and ARB strata took two pills twice daily for each dose: one tablet from the LCZ696 pack and one tablet from the comparator pack. Patients in the no RASi strata took only one tablet twice daily (LCZ696 or matching placebo). In the LCZ696 arm, patients received active LCZ696 in titrated doses from level 1 up to level 3 (50 mg, 100 mg and 200 mg twice daily orally).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sacubitril/Valsartan
    Investigational medicinal product code
    LCZ696
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LCZ696 50 mg (24mg/26mg), 100 mg (49mg/51mg) and 200 mg (97 mg/103mg)

    Investigational medicinal product name
    Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Enalapril 2.5 mg, 5 mg, and 10 mg

    Investigational medicinal product name
    Valsartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Valsartan 40 g, 80 mg, 160 mg

    Investigational medicinal product name
    Sacubitril/Valsartan
    Investigational medicinal product code
    LCZ696
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match LCZ696 50 mg, 100 mg, 200 mg

    Arm title
    		 Individualized Medical Therapy (IMT) Comparator
    Arm description
    		 Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum). Patients in the ACE stratum randomized to comparator, received enalapril in titrated doses from level 1 up to level 3 (2.5 mg, 5 mg and 10 mg twice daily). Patients in the ARB stratum randomized to comparator received valsartan in titrated doses from level 1 up to level 3 (40 mg , 80 mg and 160 mg twice daily). Patients in the no RASi stratum randomized to comparator received LCZ696 matching placebo.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Enalapril 2.5 mg, 5 mg, 10 mg

    Investigational medicinal product name
    Valsartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Valsartan 40 mg, 80 mg, 160 mg

    Investigational medicinal product name
    Sacubitril/Valsartan
    Investigational medicinal product code
    LCZ696
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match LCZ696 50 mg, 100 mg, and 200 mg

    Investigational medicinal product name
    Valsartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match Valsartan 40 mg, 80 mg 160 mg

    Number of subjects in period 1
    		Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
    Started
    1286
    1286
    Completed
    1235
    1236
    Not completed
    51
    50
         Adverse event, serious fatal
    23
    17
         Consent withdrawn by subject
    19
    25
         Physician decision
    -
    4
         Adverse event, non-fatal
    2
    3
         Technical problems
    5
    1
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sacubitril/Valsartan (LCZ696)
    Reporting group description
    		 All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients in the ACEi strata received LCZ696 or enalapril. Patients in the ARB strata received LCZ696 or valsartan. Patients in the no RASi strata received LCZ696 or matching placebo. Patients in the ACEi and ARB strata took two pills twice daily for each dose: one tablet from the LCZ696 pack and one tablet from the comparator pack. Patients in the no RASi strata took only one tablet twice daily (LCZ696 or matching placebo). In the LCZ696 arm, patients received active LCZ696 in titrated doses from level 1 up to level 3 (50 mg, 100 mg and 200 mg twice daily orally).

    Reporting group title
    Individualized Medical Therapy (IMT) Comparator
    Reporting group description
    		 Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum). Patients in the ACE stratum randomized to comparator, received enalapril in titrated doses from level 1 up to level 3 (2.5 mg, 5 mg and 10 mg twice daily). Patients in the ARB stratum randomized to comparator received valsartan in titrated doses from level 1 up to level 3 (40 mg , 80 mg and 160 mg twice daily). Patients in the no RASi stratum randomized to comparator received LCZ696 matching placebo.

    Reporting group values
    		 Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator Total
    Number of subjects
    		 1286 1286 2572
    Age Categorical
    Units: Participants
        <65 years
    		 197 221 418
        >=65 years
    		 1089 1065 2154
    Sex: Female, Male
    Units:
        Female
    		 646 658 1304
        Male
    		 640 628 1268
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 1117 1118 2235
        Black
    		 11 16 27
        Asian
    		 56 59 115
        Native American
    		 39 33 72
        Pacific Islander
    		 0 1 1
        Unknown
    		 4 3 7
        Other
    		 59 56 115

    End points

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    End points reporting groups
    Reporting group title
    Sacubitril/Valsartan (LCZ696)
    Reporting group description
    		 All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients in the ACEi strata received LCZ696 or enalapril. Patients in the ARB strata received LCZ696 or valsartan. Patients in the no RASi strata received LCZ696 or matching placebo. Patients in the ACEi and ARB strata took two pills twice daily for each dose: one tablet from the LCZ696 pack and one tablet from the comparator pack. Patients in the no RASi strata took only one tablet twice daily (LCZ696 or matching placebo). In the LCZ696 arm, patients received active LCZ696 in titrated doses from level 1 up to level 3 (50 mg, 100 mg and 200 mg twice daily orally).

    Reporting group title
    Individualized Medical Therapy (IMT) Comparator
    Reporting group description
    		 Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum). Patients in the ACE stratum randomized to comparator, received enalapril in titrated doses from level 1 up to level 3 (2.5 mg, 5 mg and 10 mg twice daily). Patients in the ARB stratum randomized to comparator received valsartan in titrated doses from level 1 up to level 3 (40 mg , 80 mg and 160 mg twice daily). Patients in the no RASi stratum randomized to comparator received LCZ696 matching placebo.

    Primary: Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) at Week 12

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    End point title
    		 Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) at Week 12
    End point description
    To demonstrate that LCZ696 is superior to individualized medical therapy for comorbidities in reducing NT-proBNP from baseline at Week 12 in patients with HFpEF
    End point type
    Primary
    End point timeframe
    Baseline, week 12
    End point values
    		 Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
    Number of subjects analysed
    1281
    1285
    Units: Percentage
        geometric mean (confidence interval 95%)
    0.8218 (0.7955 to 0.8489)
    0.9828 (0.9515 to 1.0151)
    Statistical analysis title
    		 Primary Endpoint
    Statistical analysis description
    Week 12
    Comparison groups
    Sacubitril/Valsartan (LCZ696) v Individualized Medical Therapy (IMT) Comparator
    Number of subjects included in analysis
    2566
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.8362
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7987
         upper limit
    		 0.8754

    Primary: Change from baseline in 6 minute walk distance (6MWD) at Week 24

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    End point title
    		 Change from baseline in 6 minute walk distance (6MWD) at Week 24
    End point description
    Change from baseline in 6-minute walk distance (6MWD) will be reported at Week 24. The 6 MWT will be performed in accordance with the guidelines of the American Thoracic Society 2002.
    End point type
    Primary
    End point timeframe
    Baseline, week 24
    End point values
    		 Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
    Number of subjects analysed
    1154
    1159
    Units: Meter
        arithmetic mean (confidence interval 95%)
    9.6935 (5.4310 to 13.9559)
    12.1920 (7.9202 to 16.4638)
    Statistical analysis title
    		 Primary Endpoint
    Comparison groups
    Sacubitril/Valsartan (LCZ696) v Individualized Medical Therapy (IMT) Comparator
    Number of subjects included in analysis
    2313
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4164
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.4985
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5267
         upper limit
    		 3.52297

    Secondary: Mean change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24

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    End point title
    		 Mean change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24
    End point description
    The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
    Number of subjects analysed
    1281
    1285
    Units: Scores on a scale
        arithmetic mean (confidence interval 95%)
    12.3399 (11.3151 to 13.3647)
    11.8168 (10.7922 to 12.8415)
    Statistical analysis title
    		 Secondary Enpoint
    Comparison groups
    Sacubitril/Valsartan (LCZ696) v Individualized Medical Therapy (IMT) Comparator
    Number of subjects included in analysis
    2566
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4791
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.5231
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9258
         upper limit
    		 1.972

    Secondary: Percentage of patients with ≥ 5-points deterioration in KCCQ CSS at Week 24

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    End point title
    		 Percentage of patients with ≥ 5-points deterioration in KCCQ CSS at Week 24
    End point description
    Percentage of patients with KCCQ CSS deterioration ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
    Number of subjects analysed
    1281
    1285
    Units: Percentage of participants
        number (not applicable)
    15.49
    16.69
    Statistical analysis title
    		 Secondary Endpoint
    Comparison groups
    Sacubitril/Valsartan (LCZ696) v Individualized Medical Therapy (IMT) Comparator
    Number of subjects included in analysis
    2566
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5294
    Method
    		 longitudinal binary logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8993
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6461
         upper limit
    		 1.2518

    Secondary: Percentage of patients with ≥ 5-points improvement in KCCQ CSS at Week 24

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    End point title
    		 Percentage of patients with ≥ 5-points improvement in KCCQ CSS at Week 24
    End point description
    Percentage of patients with KCCQ CSS improvement ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
    Number of subjects analysed
    1281
    1285
    Units: Percentage of participants
        number (not applicable)
    67.94
    65.70
    Statistical analysis title
    		 Secondary Endpoint
    Comparison groups
    Sacubitril/Valsartan (LCZ696) v Individualized Medical Therapy (IMT) Comparator
    Number of subjects included in analysis
    2566
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4938
    Method
    		 longitudinal binary logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.106
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8287
         upper limit
    		 1.476

    Secondary: Change from baseline in NYHA functional class at Week 24

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    End point title
    		 Change from baseline in NYHA functional class at Week 24
    End point description
    NYHA classification is a subjective physician’s assessment of patient’s functional capacity and symptomatic status and can change frequently over time. Class I - No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF Class II - Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF Class III - Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF Class IV - Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest The NYHA class change will be analyzed as a three category ordinal variable with levels: “improved”, “unchanged”, and “worsened”, defined by at least one class improvement, no change, at least one class worsening, in NYHA class, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, week 24
    End point values
    		 Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
    Number of subjects analysed
    1281
    1285
    Units: Percentage of Participants
    number (not applicable)
        Improved
    23.62
    24.00
        Unchanged
    72.23
    71.68
        Worsened
    4.15
    4.31
    Statistical analysis title
    		 Secondary Endpoint
    Comparison groups
    Sacubitril/Valsartan (LCZ696) v Individualized Medical Therapy (IMT) Comparator
    Number of subjects included in analysis
    2566
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8314
    Method
    		 Proportional cumulative odds model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.9798
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8122
         upper limit
    		 1.182

    Secondary: Change from baseline in The Short Form 36 Health Survey (SF-36) physical component summary (PCS) score at week 24

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    End point title
    		 Change from baseline in The Short Form 36 Health Survey (SF-36) physical component summary (PCS) score at week 24
    End point description
    The Short Form Health Survey (SF-36) is a widely used and extensively studied instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions. It consists of eight subscales that can be scored individually: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. This analysis will report change in symptoms as measured by the physical component summary (PCS) score at Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
    Number of subjects analysed
    1281
    1285
    Units: Scores on a scale
        arithmetic mean (confidence interval 95%)
    2.5405 (2.0787 to 3.0023)
    2.6975 (2.2360 to 3.1590)
    Statistical analysis title
    		 Secondary Endpoint
    Comparison groups
    Sacubitril/Valsartan (LCZ696) v Individualized Medical Therapy (IMT) Comparator
    Number of subjects included in analysis
    2566
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.637
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.157
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8093
         upper limit
    		 0.4953

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    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 approx. 2 years.
    Adverse event reporting additional description
    Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    Individualized Medical Therapy Comparator
    Reporting group description
    		 IMT

    Serious adverse events
    		 LCZ696 Total Individualized Medical Therapy Comparator
    Total subjects affected by serious adverse events
         subjects affected / exposed
    186 / 1280 (14.53%)
    377 / 2564 (14.70%)
    191 / 1284 (14.88%)
         number of deaths (all causes)
    23
    40
    17
         number of deaths resulting from adverse events
    1
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 1280 (0.08%)
    3 / 2564 (0.12%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    2 / 1280 (0.16%)
    2 / 2564 (0.08%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Metastases to spine
         subjects affected / exposed
    2 / 1280 (0.16%)
    2 / 2564 (0.08%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Nasal cavity cancer
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 1280 (0.16%)
    2 / 2564 (0.08%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal meningioma benign
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 1280 (0.00%)
    2 / 2564 (0.08%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract neoplasm
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Aortic stenosis
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arterial rupture
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 1280 (0.08%)
    3 / 2564 (0.12%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 1280 (0.16%)
    3 / 2564 (0.12%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 1280 (0.00%)
    2 / 2564 (0.08%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    6 / 1280 (0.47%)
    8 / 2564 (0.31%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    7 / 8
    9 / 10
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iliac artery stenosis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cardiac death
         subjects affected / exposed
    2 / 1280 (0.16%)
    2 / 2564 (0.08%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 1280 (0.00%)
    2 / 2564 (0.08%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Fatigue
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 1280 (0.00%)
    2 / 2564 (0.08%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 1280 (0.08%)
    3 / 2564 (0.12%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 1280 (0.23%)
    7 / 2564 (0.27%)
    4 / 1284 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 1280 (0.08%)
    7 / 2564 (0.27%)
    6 / 1284 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 1280 (0.00%)
    3 / 2564 (0.12%)
    3 / 1284 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood urine present
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Agitation postoperative
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    2 / 1280 (0.16%)
    2 / 2564 (0.08%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 1280 (0.00%)
    4 / 2564 (0.16%)
    4 / 1284 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured ischium
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 1280 (0.00%)
    2 / 2564 (0.08%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 1280 (0.08%)
    3 / 2564 (0.12%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Mitochondrial myopathy
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    4 / 1280 (0.31%)
    5 / 2564 (0.20%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 1280 (0.16%)
    6 / 2564 (0.23%)
    4 / 1284 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    8 / 1280 (0.63%)
    16 / 2564 (0.62%)
    8 / 1284 (0.62%)
         occurrences causally related to treatment / all
    0 / 8
    2 / 16
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    6 / 1280 (0.47%)
    13 / 2564 (0.51%)
    7 / 1284 (0.55%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 14
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    13 / 1280 (1.02%)
    30 / 2564 (1.17%)
    17 / 1284 (1.32%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 34
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    4 / 1280 (0.31%)
    6 / 2564 (0.23%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Atrial tachycardia
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    2 / 1280 (0.16%)
    5 / 2564 (0.20%)
    3 / 1284 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 1280 (0.08%)
    3 / 2564 (0.12%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    21 / 1280 (1.64%)
    52 / 2564 (2.03%)
    31 / 1284 (2.41%)
         occurrences causally related to treatment / all
    1 / 26
    1 / 62
    0 / 36
         deaths causally related to treatment / all
    0 / 5
    0 / 8
    0 / 3
    Cardiac failure acute
         subjects affected / exposed
    3 / 1280 (0.23%)
    12 / 2564 (0.47%)
    9 / 1284 (0.70%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 15
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Cardiac failure chronic
         subjects affected / exposed
    2 / 1280 (0.16%)
    3 / 2564 (0.12%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 1280 (0.16%)
    9 / 2564 (0.35%)
    7 / 1284 (0.55%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 11
    0 / 9
         deaths causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
    Cardiac perforation
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cor pulmonale acute
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    4 / 1280 (0.31%)
    5 / 2564 (0.20%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dressler's syndrome
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 1280 (0.08%)
    5 / 2564 (0.20%)
    4 / 1284 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery aneurysm
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    2 / 1280 (0.16%)
    2 / 2564 (0.08%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 1280 (0.00%)
    6 / 2564 (0.23%)
    6 / 1284 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sensory disturbance
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Syncope
         subjects affected / exposed
    2 / 1280 (0.16%)
    4 / 2564 (0.16%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    4 / 1280 (0.31%)
    4 / 2564 (0.16%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 1280 (0.16%)
    5 / 2564 (0.20%)
    3 / 1284 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular ataxia
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 1280 (0.08%)
    3 / 2564 (0.12%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye haemorrhage
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iris neovascularisation
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 1280 (0.00%)
    2 / 2564 (0.08%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 1280 (0.00%)
    2 / 2564 (0.08%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Haemorrhagic erosive gastritis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 1280 (0.16%)
    3 / 2564 (0.12%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 1280 (0.00%)
    2 / 2564 (0.08%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 1280 (0.16%)
    3 / 2564 (0.12%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic congestion
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 1280 (0.31%)
    11 / 2564 (0.43%)
    7 / 1284 (0.55%)
         occurrences causally related to treatment / all
    0 / 5
    3 / 13
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Diabetic nephropathy
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephritic syndrome
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 1280 (0.23%)
    3 / 2564 (0.12%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 1280 (0.16%)
    2 / 2564 (0.08%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 1280 (0.00%)
    2 / 2564 (0.08%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 1280 (0.00%)
    2 / 2564 (0.08%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    3 / 1280 (0.23%)
    3 / 2564 (0.12%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 1280 (0.08%)
    3 / 2564 (0.12%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 1280 (0.00%)
    4 / 2564 (0.16%)
    4 / 1284 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 1280 (0.23%)
    5 / 2564 (0.20%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 1280 (0.23%)
    3 / 2564 (0.12%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis infective
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cutaneous leishmaniasis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 1280 (0.16%)
    5 / 2564 (0.20%)
    3 / 1284 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 1280 (0.16%)
    3 / 2564 (0.12%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 1280 (0.23%)
    3 / 2564 (0.12%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 1280 (1.02%)
    26 / 2564 (1.01%)
    13 / 1284 (1.01%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 27
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Pneumonia bacterial
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 1280 (0.08%)
    2 / 2564 (0.08%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 1280 (0.16%)
    3 / 2564 (0.12%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 1280 (0.31%)
    5 / 2564 (0.20%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 1280 (0.00%)
    1 / 2564 (0.04%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 1280 (0.08%)
    3 / 2564 (0.12%)
    2 / 1284 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    3 / 1280 (0.23%)
    3 / 2564 (0.12%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 1280 (0.16%)
    3 / 2564 (0.12%)
    1 / 1284 (0.08%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 1280 (0.08%)
    1 / 2564 (0.04%)
    0 / 1284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 LCZ696 Total Individualized Medical Therapy Comparator
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    964 / 1280 (75.31%)
    1796 / 2564 (70.05%)
    832 / 1284 (64.80%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    42 / 1280 (3.28%)
    123 / 2564 (4.80%)
    81 / 1284 (6.31%)
         occurrences all number
    43
    134
    91
    Hypotension
         subjects affected / exposed
    176 / 1280 (13.75%)
    245 / 2564 (9.56%)
    69 / 1284 (5.37%)
         occurrences all number
    203
    282
    79
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    38 / 1280 (2.97%)
    59 / 2564 (2.30%)
    21 / 1284 (1.64%)
         occurrences all number
    40
    62
    22
    Oedema peripheral
         subjects affected / exposed
    43 / 1280 (3.36%)
    78 / 2564 (3.04%)
    35 / 1284 (2.73%)
         occurrences all number
    46
    84
    38
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    41 / 1280 (3.20%)
    66 / 2564 (2.57%)
    25 / 1284 (1.95%)
         occurrences all number
    42
    68
    26
    Dyspnoea
         subjects affected / exposed
    47 / 1280 (3.67%)
    93 / 2564 (3.63%)
    46 / 1284 (3.58%)
         occurrences all number
    48
    96
    48
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    27 / 1280 (2.11%)
    49 / 2564 (1.91%)
    22 / 1284 (1.71%)
         occurrences all number
    29
    54
    25
    Blood potassium increased
         subjects affected / exposed
    26 / 1280 (2.03%)
    36 / 2564 (1.40%)
    10 / 1284 (0.78%)
         occurrences all number
    33
    43
    10
    Glomerular filtration rate decreased
         subjects affected / exposed
    137 / 1280 (10.70%)
    287 / 2564 (11.19%)
    150 / 1284 (11.68%)
         occurrences all number
    153
    323
    170
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    157 / 1280 (12.27%)
    254 / 2564 (9.91%)
    97 / 1284 (7.55%)
         occurrences all number
    162
    261
    99
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    66 / 1280 (5.16%)
    131 / 2564 (5.11%)
    65 / 1284 (5.06%)
         occurrences all number
    70
    137
    67
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    44 / 1280 (3.44%)
    87 / 2564 (3.39%)
    43 / 1284 (3.35%)
         occurrences all number
    47
    95
    48
    Cardiac failure
         subjects affected / exposed
    34 / 1280 (2.66%)
    77 / 2564 (3.00%)
    43 / 1284 (3.35%)
         occurrences all number
    38
    84
    46
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    70 / 1280 (5.47%)
    133 / 2564 (5.19%)
    63 / 1284 (4.91%)
         occurrences all number
    79
    148
    69
    Headache
         subjects affected / exposed
    18 / 1280 (1.41%)
    48 / 2564 (1.87%)
    30 / 1284 (2.34%)
         occurrences all number
    19
    51
    32
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 1280 (1.33%)
    45 / 2564 (1.76%)
    28 / 1284 (2.18%)
         occurrences all number
    17
    46
    29
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    43 / 1280 (3.36%)
    85 / 2564 (3.32%)
    42 / 1284 (3.27%)
         occurrences all number
    52
    123
    71
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    27 / 1280 (2.11%)
    37 / 2564 (1.44%)
    10 / 1284 (0.78%)
         occurrences all number
    28
    40
    12
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    145 / 1280 (11.33%)
    249 / 2564 (9.71%)
    104 / 1284 (8.10%)
         occurrences all number
    148
    253
    105
    Microalbuminuria
         subjects affected / exposed
    26 / 1280 (2.03%)
    45 / 2564 (1.76%)
    19 / 1284 (1.48%)
         occurrences all number
    27
    46
    19
    Proteinuria
         subjects affected / exposed
    121 / 1280 (9.45%)
    205 / 2564 (8.00%)
    84 / 1284 (6.54%)
         occurrences all number
    124
    210
    86
    Renal failure
         subjects affected / exposed
    49 / 1280 (3.83%)
    87 / 2564 (3.39%)
    38 / 1284 (2.96%)
         occurrences all number
    54
    94
    40
    Renal impairment
         subjects affected / exposed
    148 / 1280 (11.56%)
    258 / 2564 (10.06%)
    110 / 1284 (8.57%)
         occurrences all number
    165
    293
    128
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    35 / 1280 (2.73%)
    56 / 2564 (2.18%)
    21 / 1284 (1.64%)
         occurrences all number
    36
    61
    25
    Back pain
         subjects affected / exposed
    27 / 1280 (2.11%)
    53 / 2564 (2.07%)
    26 / 1284 (2.02%)
         occurrences all number
    28
    54
    26
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    29 / 1280 (2.27%)
    64 / 2564 (2.50%)
    35 / 1284 (2.73%)
         occurrences all number
    29
    65
    36
    Influenza
         subjects affected / exposed
    33 / 1280 (2.58%)
    56 / 2564 (2.18%)
    23 / 1284 (1.79%)
         occurrences all number
    33
    57
    24
    Nasopharyngitis
         subjects affected / exposed
    35 / 1280 (2.73%)
    95 / 2564 (3.71%)
    60 / 1284 (4.67%)
         occurrences all number
    38
    100
    62
    Urinary tract infection
         subjects affected / exposed
    49 / 1280 (3.83%)
    84 / 2564 (3.28%)
    35 / 1284 (2.73%)
         occurrences all number
    55
    96
    41
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    148 / 1280 (11.56%)
    286 / 2564 (11.15%)
    138 / 1284 (10.75%)
         occurrences all number
    187
    379
    192

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jan 2017
    There were no patients randomized at the time of release of this amendment. The purpose of this amendment was to correct a typographic error in the original protocol that stated the eGFR exclusion criteria as eGFR < 15 mL/min/1.73m2 instead of the correct criteria eGFR < 30 mL/min/1.73m2.
    12 Sep 2018
    There were approximately 1095 patients randomized into the study at the time of release of this amendment. Key changes in this amendment were: To expand the EF inclusion criteria from the existing ≥ 45% to > 40%, to increase the sample size from existing 2,200 to 2,500 patients, to elevate change in 6MWD as one of the two primary endpoints in a subset of patients and remove it as a secondary endpoint, to include a testing strategy of the primary and secondary efficacy variables in the multiple testing procedure to control the family-wise Type-I error rate.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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