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    Clinical Trial Results:
    Multicenter, open-label, study to evaluate safety, tolerability, pharmacokinetics and, pharmacodynamics of LCZ696 followed by a 52-week randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared with enalapril in pediatric patients from 1 month to < 18 years of age with heart failure due to systemic left ventricle systolic dysfunction

    Summary
    EudraCT number
    		 2015-004207-22
    Trial protocol
    		 DE   FI   NL   SE   NO   ES   GB   CZ   IT   FR   BG   PL   HU   HR   AT   PT   RO  
    Global end of trial date
    03 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jul 2022
    First version publication date
    17 Jul 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLCZ696B2319
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02678312
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Novartis Pharma AG, Clinical Disclosure Office, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Novartis Pharma AG, Clinical Disclosure Office, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000316-PIP03-20
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    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
    03 Jan 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study consists of two parts (Part 1 and Part 2). The objective of Part 1 was to evaluate the way the body absorbs, distributes and removes the drug LCZ696. This would help determine the proper dose of LCZ696 for Part 2 of the study. The objective for Part 2 was to compare the effectiveness and safety of LCZ696 with enalapril in pediatric heart failure participants over 52 weeks of treatment.
    Protection of trial subjects
    Parents or guardians of all participants in this pediatric study were required to read and sign the Informed Consent Form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Nov 2016
    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: 3
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    China: 27
    Country: Number of subjects enrolled
    Croatia: 6
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    India: 16
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Jordan: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Lebanon: 10
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Saudi Arabia: 2
    Country: Number of subjects enrolled
    Singapore: 10
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Thailand: 7
    Country: Number of subjects enrolled
    Turkey: 15
    Country: Number of subjects enrolled
    United States: 137
    Worldwide total number of subjects
    393
    EEA total number of subjects
    98
    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)
    80
    Children (2-11 years)
    180
    Adolescents (12-17 years)
    133
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 393 participants were enrolled. Part 1:26 unique participants[Dose cohort 1:LCZ696 0.8 milligrams per kilogram(mg/kg)(Groups 1 and 2:age 6 to <18 years(yrs),and 1 to < 6yrs, respectively)or 0.4 mg/kg(Group 3:1 month to < 1yr), Dose cohort 2:LCZ696 3.1 mg/kg(Groups 1 and 2) or 1.6 mg/kg(Group 3)].Part 2:377 were enrolled. 10 participants from Part 1

    Pre-assignment
    Screening details
    		 Out of 26, 17 participants received drug in Dose cohort 1(Period 1). Out of 17 participants from Dose cohort 1, 9 entered Dose cohort 2(Period 2). About 9 participants directly entered Dose cohort 2. There were 2 participants from Dose cohort 2 received 3.1 mg/kg on Day 1 (Period 2) followed by 0.8 mg/kg, who entered Dose cohort S.

    Period 1
    Period 1 title
    Part 1 Open label Epoch- Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part 1: Dose Cohort 1
    Arm description
    		 Participants received LCZ696 0.4 mg/kg (age group 3 {1 month to < 1 year}) or 0.8 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696
    Investigational medicinal product code
    Other name
    sacubitiril/valsartan
    Pharmaceutical forms
    Granules for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Granules for oral solution

    Number of subjects in period 1
    		Part 1: Dose Cohort 1
    Started
    17
    Completed
    14
    Not completed
    3
         Physician decision
    1
         Adverse event, non-fatal
    1
         Lost to follow-up
    1
    Period 2
    Period 2 title
    Part 1 Open label Epoch- Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part 1: Dose Cohort 2
    Arm description
    		 Participants received LCZ696 1.6 mg/kg (age group 3 {1 month to < 1 year}) or 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696
    Investigational medicinal product code
    Other name
    sacubitiril/valsartan
    Pharmaceutical forms
    Granules for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Granules for oral solution

    Arm title
    		 Part 1: Dose Cohort S
    Arm description
    		 Participants in the dose cohort 2 who received LCZ696 3.1 mg/kg on Day 1 of period 2 and later received LCZ696 0.8 mg/kg, within period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696
    Investigational medicinal product code
    Other name
    sacubitiril/valsartan
    Pharmaceutical forms
    Granules for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Granules for oral solution

    Number of subjects in period 2
    		Part 1: Dose Cohort 2 Part 1: Dose Cohort S
    Started
    18
    2
    Completed
    18
    2
    Period 3
    Period 3 title
    Part 2 Double Blind Epoch
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part 2: LCZ696
    Arm description
    		 Participants randomised to receive LCZ696 received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696
    Investigational medicinal product code
    Other name
    sacubitiril/valsartan
    Pharmaceutical forms
    Granules, Tablet, Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    LCZ696 tablets, granules, or liquid formulation from tablets

    Arm title
    		 Part 2: Enalapril
    Arm description
    		 Participants randomised to receive enalapril received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules, Tablet, Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    LCZ696 tablets, granules, or liquid formulation from tablets

    Number of subjects in period 3
    		Part 2: LCZ696 Part 2: Enalapril
    Started
    187
    188
    Completed
    169
    164
    Not completed
    18
    24
         Adverse event, serious fatal
    8
    12
         Adverse event, non-fatal
    1
    2
         Technical Problems
    4
    2
         Subject/guardian Decision
    5
    6
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Part 1: Dose Cohort 1
    Reporting group description
    		 Participants received LCZ696 0.4 mg/kg (age group 3 {1 month to < 1 year}) or 0.8 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 1.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two participants in Part 2 who were enrolled but did not receive the study drug are not included.
    Reporting group values
    		 Part 1: Dose Cohort 1 Total
    Number of subjects
    		 17
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5.65 ( 5.283 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 9 9
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 2 2
        Asian
    		 3 3
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 3 3
        White
    		 9 9
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 2
        Not Hispanic or Latino
    		 9 9
        Unknown or Not Reported
    		 6 6
    Subject analysis sets

    Subject analysis set title
    Part 1: Dose Cohort 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 1.6 mg/kg (age group 3 {1 month to < 1 year}) or 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}, based on age, given as a single oral dose on Day 1 of period 2.

    Subject analysis set title
    Part 1: Dose Cohort S
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the dose cohort 2 who received LCZ696 3.1 mg/kg on Day 1 of period 2 and later received LCZ696 0.8 mg/kg, within period 2.

    Subject analysis set title
    Part 2: LCZ696
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomised to LCZ696 received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years} or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks.

    Subject analysis set title
    Part 2: Enalapril
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomised to enalapril received enalapril 0.15 mg/kg or 0.2 mg/kg based on age, orally, BID, and PTM LCZ696 bid for 52 weeks.

    Subject analysis set title
    LCZ696: 0.8 mg/kg (Age Group 1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.

    Subject analysis set title
    LCZ696: 0.8 mg/kg (Age Group 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.

    Subject analysis set title
    LCZ696: 3.1 mg/kg (Age Group 1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.

    Subject analysis set title
    LCZ696: 3.1 mg/kg (Age Group 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.

    Subject analysis set title
    LCZ696: 0.4 mg/kg (Age Group 3)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.

    Subject analysis set title
    LCZ696: 1.6 mg/kg (Age Group 3)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.

    Subject analysis set title
    LCZ696 (Part 1 and 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 0.4 mg/kg (age group 3) or 0.8 mg/kg (age group 1 and 2) on Day 1 of Period 1 and 1.6 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2) on Day 1 of Period 2, based on age, given as a single oral dose in Part 1. Followed by Part 1, participants were enrolled in Part 2 and received LCZ696 2.3 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2), based on age, orally, twice a day (BID) for 52 weeks in Part 2.

    Subject analysis sets values
    		 Part 1: Dose Cohort 2 Part 1: Dose Cohort S Part 2: LCZ696 Part 2: Enalapril LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3) LCZ696 (Part 1 and 2)
    Number of subjects
    18
    2
    187
    188
    7
    8
    7
    6
    4
    5
    203
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    5.60 ( 5.849 )
    1.55 ( 0.636 )
    8.00 ( 5.471 )
    8.26 ( 5.718 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    Gender categorical
    Units: Subjects
        Female
    6
    0
    98
    95
    0
    0
    0
    0
    0
    0
    0
        Male
    12
    2
    89
    93
    0
    0
    0
    0
    0
    0
    0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    1
    0
    3
    2
    0
    0
    0
    0
    0
    0
    0
        Asian
    4
    0
    57
    45
    0
    0
    0
    0
    0
    0
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Black or African American
    4
    1
    23
    25
    0
    0
    0
    0
    0
    0
    0
        White
    7
    0
    87
    93
    0
    0
    0
    0
    0
    0
    0
        More than one race
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Unknown or Not Reported
    2
    1
    17
    23
    0
    0
    0
    0
    0
    0
    0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    1
    0
    24
    15
    0
    0
    0
    0
    0
    0
    0
        Not Hispanic or Latino
    10
    1
    134
    125
    0
    0
    0
    0
    0
    0
    0
        Unknown or Not Reported
    7
    1
    28
    48
    0
    0
    0
    0
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Dose Cohort 1
    Reporting group description
    		 Participants received LCZ696 0.4 mg/kg (age group 3 {1 month to < 1 year}) or 0.8 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 1.
    Reporting group title
    Part 1: Dose Cohort 2
    Reporting group description
    		 Participants received LCZ696 1.6 mg/kg (age group 3 {1 month to < 1 year}) or 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 2.

    Reporting group title
    Part 1: Dose Cohort S
    Reporting group description
    		 Participants in the dose cohort 2 who received LCZ696 3.1 mg/kg on Day 1 of period 2 and later received LCZ696 0.8 mg/kg, within period 2.
    Reporting group title
    Part 2: LCZ696
    Reporting group description
    		 Participants randomised to receive LCZ696 received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks.

    Reporting group title
    Part 2: Enalapril
    Reporting group description
    		 Participants randomised to receive enalapril received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks.

    Subject analysis set title
    Part 1: Dose Cohort 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 1.6 mg/kg (age group 3 {1 month to < 1 year}) or 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}, based on age, given as a single oral dose on Day 1 of period 2.

    Subject analysis set title
    Part 1: Dose Cohort S
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the dose cohort 2 who received LCZ696 3.1 mg/kg on Day 1 of period 2 and later received LCZ696 0.8 mg/kg, within period 2.

    Subject analysis set title
    Part 2: LCZ696
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomised to LCZ696 received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years} or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks.

    Subject analysis set title
    Part 2: Enalapril
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomised to enalapril received enalapril 0.15 mg/kg or 0.2 mg/kg based on age, orally, BID, and PTM LCZ696 bid for 52 weeks.

    Subject analysis set title
    LCZ696: 0.8 mg/kg (Age Group 1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.

    Subject analysis set title
    LCZ696: 0.8 mg/kg (Age Group 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.

    Subject analysis set title
    LCZ696: 3.1 mg/kg (Age Group 1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.

    Subject analysis set title
    LCZ696: 3.1 mg/kg (Age Group 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.

    Subject analysis set title
    LCZ696: 0.4 mg/kg (Age Group 3)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.

    Subject analysis set title
    LCZ696: 1.6 mg/kg (Age Group 3)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.

    Subject analysis set title
    LCZ696 (Part 1 and 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received LCZ696 0.4 mg/kg (age group 3) or 0.8 mg/kg (age group 1 and 2) on Day 1 of Period 1 and 1.6 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2) on Day 1 of Period 2, based on age, given as a single oral dose in Part 1. Followed by Part 1, participants were enrolled in Part 2 and received LCZ696 2.3 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2), based on age, orally, twice a day (BID) for 52 weeks in Part 2.

    Primary: Part 1: Pharmacokinetics of LCZ696 Analytes (sacubitril, LBQ657, and valsartan): Maximum Drug Concentration in Plasma (Cmax)

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    End point title
    		 Part 1: Pharmacokinetics of LCZ696 Analytes (sacubitril, LBQ657, and valsartan): Maximum Drug Concentration in Plasma (Cmax) [1]
    End point description
    As prespecified in protocol and statistical analysis plan (SAP) the analysis of this outcome measure was done based on dose of LCZ696 administered within the different age groups. Part 1 Pharmacokinetic (PK) Set included all Part 1 eligible set (ELG1) participants with at least one dose of study drug during Part 1 of the study, at least one available valid (i.e., not flagged for exclusion) PK concentration measurement during Part 1 of the study, and with no protocol deviations with relevant impact on PK data during Part 1 of the study.
    End point type
    Primary
    End point timeframe
    Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age group 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
    Number of subjects analysed
    7
    8
    7
    6
    4
    5
    Units: nanograms per milliliter (ng/ml)
    arithmetic mean (standard deviation)
        Sacubitril
    523 ( 390 )
    179 ( 97 )
    1970 ( 1666 )
    549 ( 298 )
    124 ( 80 )
    433 ( 181 )
        LBQ657
    1951 ( 839 )
    1359 ( 711 )
    6707 ( 1887 )
    5453 ( 1032 )
    632 ( 89 )
    2326 ( 629 )
        Valsartan
    1271 ( 1011 )
    1112 ( 583 )
    4035 ( 1678 )
    4935 ( 1268 )
    440 ( 275 )
    2487 ( 1564 )
    No statistical analyses for this end point

    Primary: Part 1: Pharmacokinetics of LCZ696 Analytes (sacubitril, LBQ657, and valsartan): Time to Maximum Plasma Concentration (Tmax)

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    End point title
    		 Part 1: Pharmacokinetics of LCZ696 Analytes (sacubitril, LBQ657, and valsartan): Time to Maximum Plasma Concentration (Tmax) [2]
    End point description
    As prespecified in protocol and SAP the analysis of this outcome measure was done based on dose of LCZ696 administered within the different age groups. Participants in the Part 1 PK Set were analyzed.
    End point type
    Primary
    End point timeframe
    Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age group 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
    Number of subjects analysed
    7
    8
    7
    6
    4
    5
    Units: Hours
    arithmetic mean (standard deviation)
        Sacubitril
    1.1 ( 1.3 )
    1.2 ( 0.5 )
    0.8 ( 0.3 )
    1.2 ( 0.4 )
    1.1 ( 0.1 )
    1.0 ( 0.0 )
        LBQ657
    4.0 ( 2.0 )
    2.9 ( 1.1 )
    2.9 ( 1.1 )
    3.6 ( 3.2 )
    2.8 ( 1.6 )
    3.6 ( 0.9 )
        Valsartan
    1.7 ( 1.1 )
    2.1 ( 1.4 )
    2.6 ( 1.0 )
    1.9 ( 0.4 )
    1.8 ( 1.5 )
    1.8 ( 1.3 )
    No statistical analyses for this end point

    Primary: Part 1: Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Area Under the Plasma Concentration-time Curve from Time Zero to Infinity (AUCinf)

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    End point title
    		 Part 1: Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Area Under the Plasma Concentration-time Curve from Time Zero to Infinity (AUCinf) [3]
    End point description
    As prespecified in protocol and SAP the analysis of this outcome measure was done based on dose of LCZ696 administered within the different age groups. Participants in the Part 1 PK Set were analyzed.
    End point type
    Primary
    End point timeframe
    Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age group 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
    Number of subjects analysed
    7
    8
    7
    6
    4
    5
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Sacubitril
    690 ( 410 )
    494 ( 286 )
    3021 ( 1814 )
    1214 ( 684 )
    270 ( 182 )
    1063 ( 266 )
        LBQ657
    48264 ( 22939 )
    31042 ( 17259 )
    150440 ( 49515 )
    127625 ( 35634 )
    15835 ( 2912 )
    62377 ( 16035 )
        Valsartan
    13540 ( 12962 )
    11036 ( 7031 )
    40733 ( 21003 )
    48561 ( 21163 )
    3923 ( 1424 )
    26170 ( 16826 )
    No statistical analyses for this end point

    Primary: Part 1: Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Number of Participants With Area Under the Plasma Concentration-time Curve from Time Zero to Last (AUClast)

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    End point title
    		 Part 1: Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Number of Participants With Area Under the Plasma Concentration-time Curve from Time Zero to Last (AUClast) [4]
    End point description
    Participants in the Part 1 PK Set were analyzed.
    End point type
    Primary
    End point timeframe
    Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age group 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
    Number of subjects analysed
    7
    8
    7
    6
    4
    5
    Units: participants
    7
    8
    7
    6
    4
    5
    No statistical analyses for this end point

    Primary: Part 1: Pharmacokinetics of LCZ696 Analytes (sacubitril, LBQ657, and valsartan): Clearance from Plasma (CL/F)

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    End point title
    		 Part 1: Pharmacokinetics of LCZ696 Analytes (sacubitril, LBQ657, and valsartan): Clearance from Plasma (CL/F) [5]
    End point description
    As prespecified in protocol and SAP the analysis of this outcome measure was done based on dose of LCZ696 administered within the different age groups. CL/F was not estimated for LBQ657 as it is a metabolite. Participants in the Part 1 PK Set were analyzed.
    End point type
    Primary
    End point timeframe
    Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age group 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
    Number of subjects analysed
    7
    8
    7
    6
    4
    5
    Units: L/hr/kg
    arithmetic mean (standard deviation)
        Sacubitril
    0.73 ( 0.35 )
    1.19 ( 0.96 )
    0.63 ( 0.28 )
    1.67 ( 1.01 )
    1.19 ( 1.11 )
    1.67 ( 1.01 )
        Valsartan
    0.06 ( 0.05 )
    0.07 ( 0.09 )
    0.06 ( 0.06 )
    0.04 ( 0.01 )
    0.06 ( 0.02 )
    0.05 ( 0.03 )
    No statistical analyses for this end point

    Primary: Part 1: Pharmacokinetics of LCZ696 Analytes (sacubitril): Time Required to Drug Concentration to Decrease by Half (T 1/2)

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    End point title
    		 Part 1: Pharmacokinetics of LCZ696 Analytes (sacubitril): Time Required to Drug Concentration to Decrease by Half (T 1/2) [6]
    End point description
    As prespecified in protocol and SAP the analysis of this outcome measure was done based on dose of LCZ696 administered within the different age groups. T1/2 for other analytes of LCZ696 (LBQ657 and Valsartan) was not estimable due to short sample collection timeframe. Part 1 PK Set. The overall number of participants analyzed is the number of participants with data available for this endpoint.
    End point type
    Primary
    End point timeframe
    Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age group 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
    Number of subjects analysed
    6
    2
    6
    4
    0 [7]
    3
    Units: Hours
        median (full range (min-max))
    1.26 (0.95 to 2.36)
    1.53 (1.40 to 1.65)
    1.34 (1.16 to 1.60)
    1.51 (1.34 to 1.70)
    ( to )
    1.33 (1.16 to 1.64)
    Notes
    [7] - Data is not available as 0 participants were analysed.
    No statistical analyses for this end point

    Primary: Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma B-type Natriuretic Peptide (BNP)

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    End point title
    		 Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma B-type Natriuretic Peptide (BNP) [8]
    End point description
    Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of interest included plasma BNP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed. Part 1 PD set (PD1) included all participants who completed the Part 1 screening phase and had at least one dose of study drug during Part 1 of the study, at least one available PD measurement during Part 1 of the study, with no protocol deviations with relevant impact.9999= The 95% confidence interval (CI) was not estimable for one participant. CFB= Change From Baseline.
    End point type
    Primary
    End point timeframe
    Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
    Number of subjects analysed
    6
    6
    7
    3
    3
    4
    Units: pmol/L
    geometric mean (confidence interval 95%)
        Baseline:0 hrs pre dose (n=6,6,7,3,3,4)
    100.87 (49.84 to 204.13)
    63.80 (8.65 to 470.81)
    97.52 (51.59 to 184.32)
    120.51 (5.21 to 2787.44)
    21.20 (2.14 to 210.41)
    129.29 (9.45 to 1768.43)
        CFB:4 hrs post dose (n=6,4,7,1,3,4)
    1.31 (0.93 to 1.85)
    1.60 (0.21 to 11.95)
    1.22 (0.94 to 1.58)
    0.62 (-9999 to 9999)
    0.77 (0.56 to 1.05)
    1.09 (0.61 to 1.93)
        CFB:8 hrs post dose (n=5,4,1,1,3,2)
    1.32 (0.92 to 1.88)
    1.21 (0.21 to 7.04)
    0.97 (0.70 to 1.34)
    0.80 (-9999 to 9999)
    0.59 (0.27 to 1.30)
    0.55 (0.15 to 2.02)
    No statistical analyses for this end point

    Primary: Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma N-terminal pro-brain Natriuretic Peptide (NTproBNP)

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    End point title
    		 Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma N-terminal pro-brain Natriuretic Peptide (NTproBNP) [9]
    End point description
    Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma NTproBNP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed. Part 1 PD set. The overall number of participants analyzed is the number of participants with data available for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline (0 hrs pre dose) and optional 24 hours post dosing on Day 1 of Period 1 and Period 2
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
    Number of subjects analysed
    7
    0 [10]
    7
    0 [11]
    4
    5
    Units: pg/mL
    geometric mean (confidence interval 95%)
        Baseline:0 hrs pre dose (n=7,0,7,0,4,5)
    2385.34 (1186.13 to 4796.98)
    ( to )
    2179.94 (932.77 to 5094.69)
    ( to )
    961.76 (125.65 to 7361.70)
    5086.37 (683.53 to 37849.4)
        CFB:24 hrs post dose (n=3,0,0,0,2,2)
    0.74 (0.31 to 1.78)
    ( to )
    0 (0 to 0)
    ( to )
    0.59 (0.00 to 134.25)
    0.41 (0.34 to 0.48)
    Notes
    [10] - Data is not available as 0 participants were analysed.
    [11] - Data is not available as 0 participants were analysed.
    No statistical analyses for this end point

    Primary: Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma Cyclic Guanosine Monophosphate (cGMP)

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    End point title
    		 Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma Cyclic Guanosine Monophosphate (cGMP) [12]
    End point description
    Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma cGMP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed. Part 1 PD set. The overall number of participants analyzed is the number of participants with data available for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
    Number of subjects analysed
    7
    6
    7
    4
    2
    3
    Units: nmol/L
    geometric mean (confidence interval 95%)
        Baseline:0 hrs pre dose (n=7,6,7,4,2,3)
    18.18 (12.01 to 27.51)
    21.41 (12.83 to 35.71)
    12.20 (8.13 to 18.32)
    24.55 (18.37 to 32.82)
    13.38 (0.05 to 3883.59)
    22.84 (12.51 to 41.68)
        CFB:4 hrs post dose (n=7,6,7,4,2,3)
    1.30 (0.89 to 1.90)
    0.90 (0.50 to 1.62)
    1.54 (1.12 to 2.10)
    1.02 (0.52 to 2.01)
    0.80 (0.00 to 618.02)
    0.78 (0.27 to 2.22)
        CFB:8 hrs post dose (n=7,4,7,4,2,3)
    1.17 (0.91 to 1.50)
    0.92 (0.66 to 1.29)
    1.60 (1.10 to 2.31)
    0.40 (0.02 to 8.86)
    0.79 (0.00 to 230.10)
    0.79 (0.29 to 2.18)
    No statistical analyses for this end point

    Primary: Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Urine cGMP

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    End point title
    		 Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Urine cGMP [13]
    End point description
    Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included urine cGMP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed. Part 1 PD set. The overall number of participants analyzed is the number of participants with data available for this endpoint. 9999= The 95% CI was not estimable for one participant
    End point type
    Primary
    End point timeframe
    Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
    Number of subjects analysed
    7
    3
    6
    3
    2
    5
    Units: nmol/L
    geometric mean (confidence interval 95%)
        Baseline:0 hrs pre dose (n=7,3,6,3,1,5)
    1055.56 (352.98 to 3156.55)
    1349.91 (118.48 to 15380.33)
    914.57 (311.65 to 2683.88)
    1123.69 (75.21 to 16789.03)
    485.00 (-9999 to 9999)
    386.32 (134.04 to 1113.42)
        CFB:4 to 8 hrs hrs post dose (n=7,3,6,3,2,4)
    1.42 (0.38 to 5.32)
    0.80 (0.02 to 27.03)
    1.79 (0.65 to 4.96)
    2.17 (0.10 to 45.16)
    0.92 (0.02 to 51.75)
    1.98 (0.51 to 7.63)
    No statistical analyses for this end point

    Primary: Part 2: Percentage of Participants With Worst Event in Each Category Based on Global Ranking

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    End point title
    		 Part 2: Percentage of Participants With Worst Event in Each Category Based on Global Ranking [14]
    End point description
    Global ranking=5 categories ranking worst to best outcome: Category 1:Death; United Network for Organ Sharing(UNOS) status 1A listing for heart transplant or equivalent;ventricular assist device (VAD)/extracorporeal membrane oxygenation(ECMO)/mechanical ventilation/intra-aortic balloon pump requirement for life support at end of study.Category 2:Worsening HF(WHF)=by signs and symptoms of WHF that requires an intensification of HF therapy.Category 3:Worsened;worse New York Heart Association(NYHA)/Ross or worse Patient Global Impression of Severity(PGIS) further ranking by Pediatric Quality of Life Inventory(PedsQL) physical functioning domain.Category 4:Unchanged; unchanged NYHA/Ross and unchanged PGIS further ranking by PedsQL physical functioning domain.Category 5: Improved; improved NYHA/Ross or improved PGIS (neither can be worse) further ranking by PedsQL physical functioning domain.Participants with worst event in each category are reported here.Participants in full analysis set.
    End point type
    Primary
    End point timeframe
    Up to 52 weeks
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 Part 2: LCZ696 Part 2: Enalapril
    Number of subjects analysed
    187
    188
    Units: percentage of participants
    number (not applicable)
        Category 1
    10.16
    15.96
        Category 2
    9.63
    4.79
        Category 3
    6.95
    5.85
        Category 4
    20.86
    26.60
        Category 5
    39.57
    35.64
        Missing
    12.83
    11.17
    No statistical analyses for this end point

    Secondary: Part 1: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Part 1: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence associated with use of a drug in humans, whether or not considered drug related, that occurs after a participant provides informed consent. TEAEs during part 1 are defined as any recorded AE with its start date (recorded or imputed) later than or equal to the date of the first dose of the study drug within part 1 and its start date prior to or equal to the end date of the part 1. Part 1 Safety Analysis Set (SAF1) included all participants who completed the Part 1 screening phase and received at least one dose of study drug during Part 1 of the study.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days after last dose of study drug in Part 1
    End point values
    		 Part 1: Dose Cohort 1 Part 1: Dose Cohort 2 Part 1: Dose Cohort S
    Number of subjects analysed
    17
    18
    2
    Units: percentage of participants
        number (not applicable)
    41.18
    55.56
    50.00
    No statistical analyses for this end point

    Secondary: Part 2: Exposure-adjusted Incidence Rate of Category 1 or Category 2 Event

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    End point title
    		 Part 2: Exposure-adjusted Incidence Rate of Category 1 or Category 2 Event
    End point description
    The exposure adjusted incidence rate is calculated as number of participants with at least one event divided by total participant years across all participants. Category 1: Death; UNOS status 1A listing for heart transplant or equivalent; VAD/ECMO/mechanical ventilation/intra-aortic balloon pump requirement for life support at end of study. Category 2: WHF; defined by signs and symptoms of WHF that requires an intensification of HF therapy. Participants in the full analysis set were analyzed. Number analyzed are participants with at least one event in each category.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Part 2: LCZ696 Part 2: Enalapril
    Number of subjects analysed
    34
    33
    Units: participant per participant years
    number (confidence interval 95%)
        Category 1 or 2
    20.133 (13.9430 to 28.1344)
    20.042 (13.7960 to 28.1464)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Part 2: LCZ696 v Part 2: Enalapril
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7958 [15]
    Method
    		 Cox Proportional Hazard
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.0655
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6589
         upper limit
    		 1.7232
    Notes
    [15] - The adjusted hazard ratio and the p-values are based on Cox proportional hazard model, stratified by modified age group with treatment and NYHA/ROSS class group included as factor.

    Secondary: Part 2: Percentage of Participants With Change from Baseline in New York Heart Association (NYHA)/Ross Functional Class

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    End point title
    		 Part 2: Percentage of Participants With Change from Baseline in New York Heart Association (NYHA)/Ross Functional Class
    End point description
    NYHA classification=subjective physician's assessment of participant's functional capacity and symptomatic status and can change frequently over time.NYHA=tool that classifies participants with heart failure into one of four classes according to their degree of symptoms at rest and with activity.Class I:No limitations of physical activity.Class 2:May experience fatigue,palpitations,dyspnea,or angina during moderate exercise but not during rest.Class 3:Symptoms with minimal exertion that interfere with normal daily activity.Class 4:Unable to carry out any physical activity because they typically have symptoms of HF at rest that worsen with any exertion.Participants with change from baseline were classified as improved (shifted from higher to lower class),unchanged (no change in class) or worsened (shifted from lower to higher class).Participants in the full analysis set with available data were analyzed.n=number of participants with data available for analyses at specific timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 12, 24, 36, and 52
    End point values
    		 Part 2: LCZ696 Part 2: Enalapril
    Number of subjects analysed
    187
    188
    Units: percentage of participants
    number (not applicable)
        CFB at Week 4: Improved (n=183,184)
    14.21
    15.67
        CFB at Week 4: Unchanged (n=183,184)
    84.15
    82.61
        CFB at Week 4: Worsened (n=183,184)
    1.64
    1.63
        CFB at Week 12: Improved (n=180,180)
    23.89
    25.56
        CFB at Week 12: Unchanged (n=180,180)
    70.56
    67.78
        CFB at Week 12: Worsened (n=180,180)
    5.56
    6.67
        CFB at Week 24: Improved (n=178,172)
    26.97
    27.91
        CFB at Week 24: Unchanged (n=178,172)
    64.04
    63.95
        CFB at Week 24: Worsened (n=178,172)
    8.99
    8.14
        CFB at Week 36: Improved (n=167,170)
    29.94
    34.12
        CFB at Week 36: Unchanged (n=167,170)
    61.08
    58.24
        CFB at Week 36: Worsened (n=167,170)
    8.98
    7.65
        CFB at Week 52: Improved (n=154,159)
    37.66
    33.96
        CFB at Week 52: Unchanged (n=154,159)
    50.65
    56.60
        CFB at Week 52: Worsened (n=154,159)
    11.69
    9.43
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Participants With Change from Baseline in Patient Global Impression of Severity (PGIS) Score

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    End point title
    		 Part 2: Percentage of Participants With Change from Baseline in Patient Global Impression of Severity (PGIS) Score
    End point description
    PGIS of Heart Failure Symptoms is a 1-item questionnaire to assess the participant's impression of symptoms severity, specifically: shortness of breath, fatigue and swelling. The PGI-S asks the participant to choose one response that best describes how his/her heart failure symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-point scale, ranging from 'Not at all' (1) to 'Very severe' (5). C1 = none (good), C2 = mild, C3 = moderate, C4 = severe, C5 = very severe (bad). Percentage of participants by change in score are reported. Participants with change from baseline were classified as improved (shifted from higher to score), unchanged (no change in score) or worsened (shifted from lower to higher score). Participants in the full analysis set with available data were analyzed. Number analyzed is the number of participants with data available for analyses at specific timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 12, 24, 36, and 52
    End point values
    		 Part 2: LCZ696 Part 2: Enalapril
    Number of subjects analysed
    182
    188
    Units: percentage of participants
    number (not applicable)
        CFB at Week 4: Improved (n=174,182)
    27.01
    29.67
        CFB at Week 4: Unchanged (n=174,182)
    58.05
    59.89
        CFB at Week 4: Worsened (n=174,182)
    14.94
    10.44
        CFB at Week 12: Improved (n=172,172)
    30.90
    31.46
        CFB at Week 12: Unchanged (n=172,172)
    52.25
    55.62
        CFB at Week 12: Worsened (n=172,172)
    16.85
    12.92
        CFB at Week 24: Improved (n=174,171)
    33.33
    38.01
        CFB at Week 24: Unchanged (n=174,171)
    48.85
    48.54
        CFB at Week 24: Worsened (n=174,171)
    17.82
    13.45
        CFB at Week 36: Improved (n=162,165)
    33.33
    33.94
        CFB at Week 36: Unchanged (n=162,165)
    49.38
    52.73
        CFB at Week 36: Worsened (n=162,165)
    17.28
    13.33
        CFB at Week 52: Improved (n=152,158)
    35.53
    34.81
        CFB at Week 52: Unchanged (n=152,158)
    48.03
    47.47
        CFB at Week 52: Worsened (n=152,158)
    16.45
    17.72
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Population PK of LCZ696 analytes: Clearance from Plasma (CL)

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    End point title
    		 Part 1 and Part 2: Population PK of LCZ696 analytes: Clearance from Plasma (CL)
    End point description
    The population PK approach was used to describe the pharmacokinetics of LCZ696 analytes. The population PK analysis dataset included all participants from Part 1 and 2 for whom plasma concentrations were available. Number analyzed are participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Part 1: Age group 1- Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3- Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Part 2: Weeks 2, 8, 12, 52
    End point values
    		 LCZ696 (Part 1 and 2)
    Number of subjects analysed
    203
    Units: L/h
    arithmetic mean (standard deviation)
        Sacubitril (n=202)
    25.93 ( 19.29 )
        LBQ657 (n=202)
    0.44 ( 0.31 )
        Valsartan
    1.97 ( 1.69 )
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Population PK of LCZ696 analytes: Volume of Distribution in Steady State

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    End point title
    		 Part 1 and Part 2: Population PK of LCZ696 analytes: Volume of Distribution in Steady State
    End point description
    The population PK approach was used to describe the pharmacokinetics of LCZ696 analytes. The population PK analysis dataset included all participants from Part 1 and 2 for whom plasma concentrations were available. Number analyzed are participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Part 1: Age group 1- Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3- Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Part 2: Weeks 2, 8, 12, 52
    End point values
    		 LCZ696 (Part 1 and 2)
    Number of subjects analysed
    203
    Units: L/Kg
    arithmetic mean (standard deviation)
        Sacubitril (n=202)
    4.67 ( 5.84 )
        LBQ657 (n=202)
    0.34 ( 0.12 )
        Valsartan
    0.68 ( 0.29 )
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Population PK of LCZ696 Analytes: Absorption Rate Constant (Ka)

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    End point title
    		 Part 1 and Part 2: Population PK of LCZ696 Analytes: Absorption Rate Constant (Ka)
    End point description
    The population PK approach was used to describe the pharmacokinetics of LCZ696 analytes. The population PK analysis dataset included all participants from Part 1 and 2 for whom plasma concentrations were available. Number analyzed are participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Part 1: Age group 1- Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3- Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Part 2: Weeks 2, 8, 12, 52
    End point values
    		 LCZ696 (Part 1 and 2)
    Number of subjects analysed
    203
    Units: 1/hour
    arithmetic mean (standard deviation)
        Sacubitril (n=202)
    1.25 ( 0.01 )
        LBQ657 (n=202)
    1.04 ( 1.34 )
        Valsartan
    1.42 ( 0.92 )
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Population PK of LCZ696 Analytes: Maximum Drug Concentration in Plasma at Steady State (Cmax,ss)

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    End point title
    		 Part 1 and Part 2: Population PK of LCZ696 Analytes: Maximum Drug Concentration in Plasma at Steady State (Cmax,ss)
    End point description
    The population PK approach was used to describe the pharmacokinetics of LCZ696 analytes. The population PK analysis dataset included all participants from Part 1 and 2 for whom plasma concentrations were available. Number analyzed are participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Part 1: Age group 1- Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3- Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Part 2: Weeks 2, 8, 12, 52
    End point values
    		 LCZ696 (Part 1 and 2)
    Number of subjects analysed
    203
    Units: ng/mL
    arithmetic mean (standard deviation)
        Sacubitril (n=202)
    1348 ( 627 )
        LBQ657 (n=202)
    10153 ( 3591 )
        Valsartan (n=203)
    3861 ( 1770 )
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Population PK of LCZ696 Analytes: Time required to drug concentration to decrease by half (T 1/2)

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    End point title
    		 Part 1 and Part 2: Population PK of LCZ696 Analytes: Time required to drug concentration to decrease by half (T 1/2)
    End point description
    The population PK approach was used to describe the pharmacokinetics of LCZ696 analytes. The population PK analysis dataset included all participants from Part 1 and 2 for whom plasma concentrations were available. Number analyzed are participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Part 1: Age group 1- Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3- Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Part 2: Weeks 2, 8, 12, 52
    End point values
    		 LCZ696 (Part 1 and 2)
    Number of subjects analysed
    203
    Units: hours
    median (full range (min-max))
        Sacubitril (n=202)
    8.51 (1.87 to 199.55)
        LBQ657 (n=202)
    18.21 (6.08 to 107.47)
        Valsartan
    7.96 (2.33 to 81.65)
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Population PK of LCZ696 Analytes: Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss)

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    End point title
    		 Part 1 and Part 2: Population PK of LCZ696 Analytes: Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss)
    End point description
    The population PK approach was used to describe the pharmacokinetics of LCZ696 analytes. The population PK analysis dataset included all participants from Part 1 and 2 for whom plasma concentrations were available. Number analyzed are participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Part 1: Age group 1- Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3- Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Part 2: Weeks 2, 8, 12, 52
    End point values
    		 LCZ696 (Part 1 and 2)
    Number of subjects analysed
    203
    Units: ng/mL
    arithmetic mean (standard deviation)
        Sacubitril (n=202)
    63 ( 141 )
        LBQ657 (n=202)
    6442 ( 3474 )
        Valsartan (n=203)
    1442 ( 1564 )
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Population PK of LCZ696 Analytes: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady State (AUCtau,ss)

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    End point title
    		 Part 1 and Part 2: Population PK of LCZ696 Analytes: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady State (AUCtau,ss)
    End point description
    The population PK approach was used to describe the pharmacokinetics of LCZ696 analytes. The population PK analysis dataset included all participants from Part 1 and 2 for whom plasma concentrations were available. Number analyzed are participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Part 1: Age group 1- Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3- Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Part 2: Weeks 2, 8, 12, 52
    End point values
    		 LCZ696 (Part 1 and 2)
    Number of subjects analysed
    203
    Units: ng/mL*h
    arithmetic mean (standard deviation)
        Sacubitril (n=202)
    2179 ( 2241 )
        LBQ657 (n=202)
    98906 ( 41944 )
        Valsartan (n=203)
    28672 ( 19686 )
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Part 2: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)
    End point description
    An AE is any untoward medical occurrence associated with use of a drug in humans, whether or not considered drug related, that occurs after a participant provides informed consent. TEAEs during part 2 are defined as any recorded AE with its start date (recorded or imputed) later than or equal to the date of the first dose of the study drug within part 2and its start date prior to or equal to the end date of part 2. Part 2: Safety Set (SAF2) included randomized participants who received at least one dose of study drug. Participants were analyzed according to the treatment actually received. The treatment actually received was considered identical to the randomized treatment if the participant had received at least one dose of the randomized treatment.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days after last dose of study drug in Part 2 (up to 56 weeks)
    End point values
    		 Part 2: LCZ696 Part 2: Enalapril
    Number of subjects analysed
    187
    188
    Units: percentage of participant
        number (not applicable)
    88.77
    87.77
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part 1: From first dose to 30 days after last dose of study drug in Part 1; Part 2: From first dose to 30 days after last dose of study drug in Part 2 (up to 56 weeks)
    Adverse event reporting additional description
    Part 1: Safety Set(SAF1) included participants who completed the Part 1 screening phase and received at least one dose of study drug during Part 1 of the study. Part 2:Safety Set(SAF2) included randomized participants who received at least one dose of study drug. Participants were analyzed according to the treatment actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Part 1: Dose Cohort 1
    Reporting group description
    		 Participants received LCZ696 0.4 mg/kg (age group 3 {1 month to < 1 year}) or 0.8 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}, based on age, given as a single oral dose on Day 1 of period 1.

    Reporting group title
    Part 1: Dose Cohort 2
    Reporting group description
    		 Participants received LCZ696 1.6 mg/kg (age group 3 {1 month to < 1 year}) or 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}, based on age, given as a single oral dose on Day 1 of period 2.

    Reporting group title
    Part 1: Dose Cohort S
    Reporting group description
    		 Participants in the dose cohort 2 who received LCZ696 3.1 mg/kg on Day 1 of period 2 and later received LCZ696 0.8 mg/kg, within period 2.

    Reporting group title
    Part 2: LCZ696
    Reporting group description
    		 Participants received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years} or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks.

    Reporting group title
    Part 2: Enalapril
    Reporting group description
    		 Participants received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years} or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks.

    Serious adverse events
    		 Part 1: Dose Cohort 1 Part 1: Dose Cohort 2 Part 1: Dose Cohort S Part 2: LCZ696 Part 2: Enalapril
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    69 / 187 (36.90%)
    62 / 188 (32.98%)
         number of deaths (all causes)
    0
    0
    0
    8
    12
         number of deaths resulting from adverse events
    0
    0
    0
    0
    1
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Immune system disorders
    Heart transplant rejection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthopnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Tachypnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac output decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronavirus test positive
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Human rhinovirus test positive
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental exposure to product
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Adrenogenital syndrome
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    3 / 188 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    4 / 188 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 4
    Cardiac disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    24 / 187 (12.83%)
    23 / 188 (12.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 34
    3 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    Cardiac failure acute
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    4 / 188 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    3 / 188 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular dysfunction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Akinesia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal ganglia infarction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Juvenile myoclonic epilepsy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuromyopathy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    4 / 188 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    5 / 187 (2.67%)
    4 / 188 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal artery stenosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Renal impairment
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Neck mass
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    5 / 187 (2.67%)
    4 / 188 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral sepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Feeding intolerance
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Part 1: Dose Cohort 1 Part 1: Dose Cohort 2 Part 1: Dose Cohort S Part 2: LCZ696 Part 2: Enalapril
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 17 (35.29%)
    10 / 18 (55.56%)
    1 / 2 (50.00%)
    161 / 187 (86.10%)
    156 / 188 (82.98%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Hypotension
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 18 (11.11%)
    0 / 2 (0.00%)
    21 / 187 (11.23%)
    22 / 188 (11.70%)
         occurrences all number
    1
    2
    0
    31
    36
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    3
    2
    Chest discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    2
    1
    Chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    7 / 187 (3.74%)
    7 / 188 (3.72%)
         occurrences all number
    0
    0
    0
    8
    10
    Face oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Fatigue
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 2 (50.00%)
    19 / 187 (10.16%)
    14 / 188 (7.45%)
         occurrences all number
    0
    2
    2
    19
    19
    Medical device pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    0
    2
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    7 / 187 (3.74%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    8
    2
    Peripheral swelling
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 2 (50.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    1
    1
    0
    2
    Pyrexia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    36 / 187 (19.25%)
    34 / 188 (18.09%)
         occurrences all number
    0
    1
    0
    49
    50
    Swelling face
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 2 (50.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    1
    1
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Dysmenorrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    2
    5
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    5
    2
    Cough
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 2 (50.00%)
    36 / 187 (19.25%)
    38 / 188 (20.21%)
         occurrences all number
    0
    1
    1
    57
    49
    Dyspnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    6 / 187 (3.21%)
    4 / 188 (2.13%)
         occurrences all number
    0
    0
    0
    6
    4
    Dyspnoea exertional
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Epistaxis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    9 / 187 (4.81%)
    6 / 188 (3.19%)
         occurrences all number
    1
    0
    0
    11
    9
    Nasal congestion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    4 / 188 (2.13%)
         occurrences all number
    0
    0
    0
    5
    5
    Oropharyngeal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    9 / 187 (4.81%)
    5 / 188 (2.66%)
         occurrences all number
    0
    0
    0
    9
    6
    Pneumothorax
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    2
    1
    Productive cough
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    5 / 187 (2.67%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    5
    1
    Respiratory disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    2
    2
    Rhinitis allergic
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    4 / 188 (2.13%)
         occurrences all number
    0
    0
    0
    2
    4
    Rhinorrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    7 / 187 (3.74%)
    7 / 188 (3.72%)
         occurrences all number
    0
    0
    0
    9
    7
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    1
    3
    Wheezing
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    2
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    5 / 188 (2.66%)
         occurrences all number
    0
    0
    0
    5
    5
    Depression
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    2
    1
    Insomnia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    5
    5
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    3
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    3
    1
    Blood creatine increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    6 / 187 (3.21%)
    5 / 188 (2.66%)
         occurrences all number
    0
    0
    0
    6
    8
    Blood potassium increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    3
    2
    Blood urea increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    1
    0
    0
    2
    1
    Blood uric acid increased
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    1
    1
    0
    1
    2
    Body temperature increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    0 / 188 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    9 / 187 (4.81%)
    12 / 188 (6.38%)
         occurrences all number
    0
    0
    0
    10
    13
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    SARS-CoV-2 test negative
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    6 / 187 (3.21%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    8
    1
    Weight decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    4 / 188 (2.13%)
         occurrences all number
    0
    0
    0
    0
    4
    Weight increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    3
    2
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Contusion
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    2 / 188 (1.06%)
         occurrences all number
    0
    1
    0
    3
    2
    Fall
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    5 / 188 (2.66%)
         occurrences all number
    0
    1
    0
    3
    7
    Lip injury
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Procedural pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    4 / 188 (2.13%)
         occurrences all number
    0
    0
    0
    0
    4
    Skin abrasion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    2
    3
    Skin laceration
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    3
    1
    Arrhythmia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Bradycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Cardiac failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    5 / 187 (2.67%)
    6 / 188 (3.19%)
         occurrences all number
    0
    0
    0
    6
    6
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Palpitations
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    4
    1
    Tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    4 / 188 (2.13%)
         occurrences all number
    0
    0
    0
    0
    5
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    4 / 188 (2.13%)
         occurrences all number
    0
    0
    0
    0
    4
    Ventricular tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    4
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    23 / 187 (12.30%)
    15 / 188 (7.98%)
         occurrences all number
    0
    0
    0
    29
    22
    Headache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    22 / 187 (11.76%)
    20 / 188 (10.64%)
         occurrences all number
    0
    0
    0
    45
    24
    Hypersomnia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Migraine
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    2
    1
    Paraesthesia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Presyncope
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    2
    5
    Syncope
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 18 (11.11%)
    0 / 2 (0.00%)
    7 / 187 (3.74%)
    5 / 188 (2.66%)
         occurrences all number
    0
    2
    0
    7
    5
    Lymphadenopathy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    3
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    4
    3
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Abdominal distension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Abdominal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    15 / 187 (8.02%)
    11 / 188 (5.85%)
         occurrences all number
    0
    0
    0
    36
    13
    Abdominal pain upper
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    6 / 187 (3.21%)
    9 / 188 (4.79%)
         occurrences all number
    0
    0
    0
    7
    10
    Constipation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    6 / 187 (3.21%)
    7 / 188 (3.72%)
         occurrences all number
    0
    0
    0
    12
    8
    Dental caries
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Diarrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    25 / 187 (13.37%)
    23 / 188 (12.23%)
         occurrences all number
    0
    0
    0
    35
    26
    Dyspepsia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Enteritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    2
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    5 / 187 (2.67%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    5
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Mouth ulceration
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Nausea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    9 / 187 (4.81%)
    9 / 188 (4.79%)
         occurrences all number
    0
    0
    0
    9
    13
    Toothache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    5 / 187 (2.67%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    5
    2
    Vomiting
         subjects affected / exposed
    1 / 17 (5.88%)
    4 / 18 (22.22%)
    1 / 2 (50.00%)
    33 / 187 (17.65%)
    37 / 188 (19.68%)
         occurrences all number
    1
    4
    1
    51
    52
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    3
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Dermatitis allergic
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Dermatitis contact
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Dry skin
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Ecchymosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    3
    2
    Eczema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    6
    1
    Erythema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    4
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    3
    1
    Ingrowing nail
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    3
    Petechiae
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Pruritus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    2
    3
    Rash
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    5 / 187 (2.67%)
    6 / 188 (3.19%)
         occurrences all number
    0
    0
    0
    6
    6
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    3
    2
    Polyuria
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Renal failure
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    1 / 188 (0.53%)
         occurrences all number
    1
    1
    0
    1
    1
    Renal impairment
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    5
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    0
    6
    1
    Back pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    6 / 187 (3.21%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    7
    3
    Muscle spasms
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Myalgia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    2
    1
    Pain in extremity
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    6 / 187 (3.21%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    6
    3
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    0
    3
    Atypical pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Bronchitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    12 / 187 (6.42%)
    8 / 188 (4.26%)
         occurrences all number
    0
    0
    0
    15
    11
    COVID-19
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    6 / 187 (3.21%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    6
    2
    Candida infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Ear infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    2
    5
    Exanthema subitum
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    9 / 187 (4.81%)
    11 / 188 (5.85%)
         occurrences all number
    0
    0
    0
    11
    13
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Gastroenteritis viral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    3
    3
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    2
    3
    Influenza
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    11 / 187 (5.88%)
    12 / 188 (6.38%)
         occurrences all number
    0
    0
    0
    15
    13
    Nasopharyngitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    29 / 187 (15.51%)
    17 / 188 (9.04%)
         occurrences all number
    0
    0
    0
    57
    32
    Oral herpes
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    1
    3
    Otitis media
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    5 / 187 (2.67%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    5
    3
    Otitis media acute
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    2
    2
    Pharyngitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    6 / 187 (3.21%)
    5 / 188 (2.66%)
         occurrences all number
    0
    0
    0
    7
    5
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    0 / 188 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    3
    3
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    1
    0
    0
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    2
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    5 / 188 (2.66%)
         occurrences all number
    0
    0
    0
    4
    5
    Rhinitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    7 / 187 (3.74%)
    10 / 188 (5.32%)
         occurrences all number
    0
    1
    0
    12
    15
    Sinusitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    3 / 187 (1.60%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    4
    2
    Tonsillitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    1
    3
    Tracheitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 18 (16.67%)
    1 / 2 (50.00%)
    37 / 187 (19.79%)
    35 / 188 (18.62%)
         occurrences all number
    0
    3
    1
    62
    62
    Urinary tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    0 / 188 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Viral infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    5 / 187 (2.67%)
    4 / 188 (2.13%)
         occurrences all number
    0
    0
    0
    5
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    1 / 187 (0.53%)
    3 / 188 (1.60%)
         occurrences all number
    0
    1
    0
    1
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    9 / 187 (4.81%)
    1 / 188 (0.53%)
         occurrences all number
    0
    0
    0
    10
    1
    Dehydration
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    2 / 187 (1.07%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    2
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Hyperkalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    6 / 187 (3.21%)
    6 / 188 (3.19%)
         occurrences all number
    0
    0
    0
    7
    8
    Hypokalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 2 (0.00%)
    4 / 187 (2.14%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    0
    4
    1
    Iron deficiency
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 2 (0.00%)
    0 / 187 (0.00%)
    3 / 188 (1.60%)
         occurrences all number
    0
    0
    0
    0
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2016
    The following changes were made in amendment 1: - Added second dose to Part 1 study design and other relevant sections. Assessment schedule, Safety, pharmacokinetic (PK), and pharmacodynamic (PD) data review have been revised accordingly. - Total of six participants per dose for each age group is planned. Two doses are being assessed in Groups 1 and 2, and one dose is being assessed in Group 3. - For the PedsQL scale, the chronic version (one month recall period) was replaced with the acute version (7 days recall period). The reason for this change is that the patient reported assessment of 7 days is considered more appropriate compared to 1 month for pediatric heart failure patients. Added text indicating that the PedsQL Physical Functioning module will be used for the primary Global Rank endpoint only for Group 1 (6 to <18 years old). - Added safety and tolerability Secondary objective in Part 1.
    10 Jul 2017
    The following changes were made in amendment 2: - Total of six participants per dose for each age group is planned. Two doses are being assessed in Groups 1 and 2, and one dose is being assessed in Group 3. Updated and corrected blood volumes for PK and PD sampling in Part 1.
    01 Oct 2018
    The following changes were made in amendment 3: - For Part 1 Group 3 participants, removed the single dose level of LCZ696 0.8 mg/kg and replaced it with two dose levels: LCZ696 0.4 mg/kg and LCZ696 1.6 mg/kg. Inclusion criterion 7 has been modified accordingly. Total of approximately 4 observations per dose (approximately 8 in total) and a minimum of 4 participants is planned for Group 3 in Part 1. - Added to Part 2 of the study, a steady-state Sparse PK blood collection visit, applicable to a subset of participants in Group 2 (approximately 24 participants of whom approximately 12 participants are expected to be randomized to LCZ696) who agree to participate. These participants will also have NTproBNP collected at the time of the Sparse PK visit.
    04 Feb 2019
    The following changes were made in amendment 4: - Data Analysis Section: added the interim biomarker analysis.
    18 Sep 2020
    The following changes were made in amendment 5: - Added target dose level (Dose Level 4x) for Age Group 3. Added statement enabling Age Group 3 participants that turn 1 year old during the study, to be up-titrated to Group 3 Dose Level 5x (LCZ696 3.1 mg/kg bid/ enalapril 0.2 mg/kg bid). Data Analysis Section: Clarified age groups for Part 1 analysis. Added modified age groups for Part 2 analysis. - Removed enrollment target of 25% Angiotensin converting enzyme inhibitor (ACEI/ARB) naïve participants. Removed requirement for 20% of the total n of 360 (72 participants) to be randomized and included for analysis in each age group. Removed required number of participants (80) with an event in Category 1 or 2 (in two places in this section). Clarified Part 1 age groups. Clarified target dose for Age Groups 1 and 2 (Dose Level 4) and added target dose level (Dose Level 4x) for Age Group 3. Modified Tables 3-4, 3-5 and 3-6. Added safety monitoring requirements for Part 2 Age Group 3 participants. Added details enabling Age Group 3 participants that turn 1 year old during the study, to be up-titrated to Group 3 Dose Level 5x (LCZ696 3.1 mg/kg bid/ enalapril 0.2 mg/kg bid). Also added a statement indicating that a scheduled or unscheduled visit may be used for these up-titrations and added detailed criteria for up-titration. Note: References to dose levels 1 through 4 throughout the protocol have been changed to dose levels 1x to 4x for Age Group 3 participants.
    08 Oct 2020
    The following changes were made in amendment 6: - Total daily dose levels of commonly prescribed ACEI/ARBs to guide selection of the study medication starting dose: Clarified “low” and “higher” ACEI/ARB doses in the text. Removed dose levels 1x through 4x of commonly prescribed ACEI/ARBs. Part 2 (Efficacy) Study drug dose levels for double-blind enalapril and LCZ696 for age group 3: The enalapril dose for Dose Level 2x has been corrected to 0.075 mg/kg bid.
    26 Oct 2021
    The following changes were made in amendment 7: - Urgent safety measure (USM): Details regarding the USM, instructions for participants impacted by the USM and USM implications regarding data collection and study results.

    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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