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    Clinical Trial Results:
    A randomized, study in healthy subjects to determine the bioavailability of 200 mg LCZ696 mini-tablet compared to the 200 mg LCZ696 final market image tablet

    Summary
    EudraCT number
    		 2017-001803-57
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    05 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Dec 2017
    First version publication date
    22 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCZ696B2126
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111 ,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111 ,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000316-PIP02-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the relative bioavailability of the LCZ696 200 mg mini-tablets compared to the LCZ696 200 mg final market image (FMI) tablet after single administration in healthy subjects under fasted condition. To evaluate the effect of a small amount of soft food (vanilla pudding) on the bioavailability of a single oral dose of LCZ696 200 mg mini-tablets in healthy subjects under fasted condition. To evaluate the effect of a high fat meal on the bioavailability of a single oral dose of LCZ696 200 mg mini-tablets sprinkled on vanilla pudding in healthy subjects.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 May 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This was an open-labeled, randomized, four-sequence, four-period, crossover study in healthy subjects. The study consisted of a maximum 21-day Screening period and four treatment periods.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Sequence 1
    Arm description
    		 Sequence 1: A/B/C/D; Treatment A: LCZ696 200 mg FMI tablet Treatment B: LCZ696 200 mg mini-tablets Treatment C: LCZ696 200 mg mini-tablets with pudding Treatment D: LCZ696 200 mg mini-tablets with pudding and high fat meal
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696 FMI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication was administered by the study center personnel with 240 mL of water in the morning following an overnight fast of at least 10 h.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication was administered by the study center personnel with 240 mL of water in the morning following an overnight fast of at least 10 h.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets/pudding
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication (mini-tablets) sprinkled on a tablespoon of vanilla pudding was administered by the study center personnel in the morning followed by 240 mL of water under fasted condition.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets/pudding/high fat meal
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered LCZ696 200 mg mini-tablets sprinkled on a tablespoon of vanilla pudding 30 minutes after the start of high fat breakfast (800-1000 kcal; ~15% protein, ~25% carbohydrate and ~60% fat), followed by 240 mL of water.

    Arm title
    		 Sequence 2
    Arm description
    		 Sequence 2: B/D/A/C; Treatment A: LCZ696 200 mg FMI tablet Treatment B: LCZ696 200 mg mini-tablets Treatment C: LCZ696 200 mg mini-tablets with pudding Treatment D: LCZ696 200 mg mini-tablets with pudding and high fat meal
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696 FMI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication was administered by the study center personnel with 240 mL of water in the morning following an overnight fast of at least 10 h.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication was administered by the study center personnel with 240 mL of water in the morning following an overnight fast of at least 10 h.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets/pudding
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication (mini-tablets) sprinkled on a tablespoon of vanilla pudding was administered by the study center personnel in the morning followed by 240 mL of water under fasted condition.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets/pudding/high fat meal
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered LCZ696 200 mg mini-tablets sprinkled on a tablespoon of vanilla pudding 30 minutes after the start of high fat breakfast (800-1000 kcal; ~15% protein, ~25% carbohydrate and ~60% fat), followed by 240 mL of water.

    Arm title
    		 Sequence 3
    Arm description
    		 Sequence 3: C/A/D/B; Treatment A: LCZ696 200 mg FMI tablet Treatment B: LCZ696 200 mg mini-tablets Treatment C: LCZ696 200 mg mini-tablets with pudding Treatment D: LCZ696 200 mg mini-tablets with pudding and high fat meal
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696 FMI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication was administered by the study center personnel with 240 mL of water in the morning following an overnight fast of at least 10 h.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication was administered by the study center personnel with 240 mL of water in the morning following an overnight fast of at least 10 h.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets/pudding
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication (mini-tablets) sprinkled on a tablespoon of vanilla pudding was administered by the study center personnel in the morning followed by 240 mL of water under fasted condition.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets/pudding/high fat meal
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered LCZ696 200 mg mini-tablets sprinkled on a tablespoon of vanilla pudding 30 minutes after the start of high fat breakfast (800-1000 kcal; ~15% protein, ~25% carbohydrate and ~60% fat), followed by 240 mL of water.

    Arm title
    		 Sequence 4
    Arm description
    		 Sequence 4: D/C/B/A; Treatment A: LCZ696 200 mg FMI tablet Treatment B: LCZ696 200 mg mini-tablets Treatment C: LCZ696 200 mg mini-tablets with pudding Treatment D: LCZ696 200 mg mini-tablets with pudding and high fat meal
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696 FMI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication was administered by the study center personnel with 240 mL of water in the morning following an overnight fast of at least 10 h.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication was administered by the study center personnel with 240 mL of water in the morning following an overnight fast of at least 10 h.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets/pudding
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study medication (mini-tablets) sprinkled on a tablespoon of vanilla pudding was administered by the study center personnel in the morning followed by 240 mL of water under fasted condition.

    Investigational medicinal product name
    LCZ696 200 mg mini-tablets/pudding/high fat meal
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered LCZ696 200 mg mini-tablets sprinkled on a tablespoon of vanilla pudding 30 minutes after the start of high fat breakfast (800-1000 kcal; ~15% protein, ~25% carbohydrate and ~60% fat), followed by 240 mL of water.

    Number of subjects in period 1
    		Sequence 1 Sequence 2 Sequence 3 Sequence 4
    Started
    10
    10
    10
    10
    Completed
    9
    10
    10
    10
    Not completed
    1
    0
    0
    0
         Protocol deviation
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    		 -

    Reporting group values
    		 Overall Period Total
    Number of subjects
    		 40 40
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 40 40
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.0 ( 8.48 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 30 30

    End points

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    End points reporting groups
    Reporting group title
    Sequence 1
    Reporting group description
    		 Sequence 1: A/B/C/D; Treatment A: LCZ696 200 mg FMI tablet Treatment B: LCZ696 200 mg mini-tablets Treatment C: LCZ696 200 mg mini-tablets with pudding Treatment D: LCZ696 200 mg mini-tablets with pudding and high fat meal

    Reporting group title
    Sequence 2
    Reporting group description
    		 Sequence 2: B/D/A/C; Treatment A: LCZ696 200 mg FMI tablet Treatment B: LCZ696 200 mg mini-tablets Treatment C: LCZ696 200 mg mini-tablets with pudding Treatment D: LCZ696 200 mg mini-tablets with pudding and high fat meal

    Reporting group title
    Sequence 3
    Reporting group description
    		 Sequence 3: C/A/D/B; Treatment A: LCZ696 200 mg FMI tablet Treatment B: LCZ696 200 mg mini-tablets Treatment C: LCZ696 200 mg mini-tablets with pudding Treatment D: LCZ696 200 mg mini-tablets with pudding and high fat meal

    Reporting group title
    Sequence 4
    Reporting group description
    		 Sequence 4: D/C/B/A; Treatment A: LCZ696 200 mg FMI tablet Treatment B: LCZ696 200 mg mini-tablets Treatment C: LCZ696 200 mg mini-tablets with pudding Treatment D: LCZ696 200 mg mini-tablets with pudding and high fat meal

    Subject analysis set title
    LCZ696 200 mg mini-tablets
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The investigational drug, LCZ696 3.125 mg mini-tablets; 200 mg dose was given as 64 mini-tablets.

    Subject analysis set title
    LCZ696 200 mg FMI tablet
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The investigational drug, LCZ696 200 mg final market image (FMI) tablet.

    Subject analysis set title
    LCZ696 200 mg mini-tablets with pudding
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Study medication sprinkled on a tablespoon of vanilla pudding was administered by the study center personnel in the morning followed by 240 mL of water under fasted condition.

    Subject analysis set title
    LCZ696 200 mg mini-tablets with pudding and high fat meal
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were administered LCZ696 200 mg mini-tablets sprinkled on a tablespoon of vanilla pudding by mouth 30 minutes after the start of high fat breakfast. Study drug was administered with 240 mL of water.

    Primary: Adjusted Geometric mean of AUCinf for comparison of mini-tablets and FMI tablets for LCZ696 – Completers

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    End point title
    		 Adjusted Geometric mean of AUCinf for comparison of mini-tablets and FMI tablets for LCZ696 – Completers
    End point description
    AUCinf measures the area under the plasma concentration-time curve from time zero to infinity [ng*h/mL].
    End point type
    Primary
    End point timeframe
    Pre-dose (0 h) until 96 h postdose. Additional outpatient PK blood sampling at 48, 72, and 96 h post-dose.
    End point values
    		 LCZ696 200 mg mini-tablets LCZ696 200 mg FMI tablet
    Number of subjects analysed
    40 [1]
    40 [2]
    Units: ng*h/mL
    number (not applicable)
        Analyte AHU377
    1914
    2002
        Analyte LBQ657
    79673
    81590
        Analyte Valsartan
    21414
    19251
    Notes
    [1] - PK analysis set n= 40, 40, 37
    [2] - PK analysis set n= 40, 40, 37
    Statistical analysis title
    		 Comparison result - AUCinf AHU377
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg FMI tablet
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.96
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1
    Statistical analysis title
    		 Comparison result - AUCinf LBQ657
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg FMI tablet
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.98
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 0.99
    Statistical analysis title
    		 Comparison result - AUCinf Valsartan
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg FMI tablet
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.11
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.24

    Primary: Adjusted Geometric mean of AUClast for comparison of mini-tablets and FMI tablets for LCZ696 – Completers

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    End point title
    		 Adjusted Geometric mean of AUClast for comparison of mini-tablets and FMI tablets for LCZ696 – Completers
    End point description
    AUClast measures the area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration [ng*h/mL].
    End point type
    Primary
    End point timeframe
    Pre-dose (0 h) until 96 h postdose. Additional outpatient PK blood sampling at 48, 72, and 96 h postdose.
    End point values
    		 LCZ696 200 mg mini-tablets LCZ696 200 mg FMI tablet
    Number of subjects analysed
    40 [3]
    40 [4]
    Units: ng*h/mL
    number (not applicable)
        Analyte AHU377
    1910
    1997
        Analyte LBQ657
    79005
    80929
        Analyte Valsartan
    20772
    18798
    Notes
    [3] - PK analysis set
    [4] - PK analysis set
    Statistical analysis title
    		 Comparison result - AUClast AHU377
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg FMI tablet
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.96
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1
    Statistical analysis title
    		 Comparison result - AUClast LBQ657
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg FMI tablet
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.98
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 0.99
    Statistical analysis title
    		 Comparison result - AUClast Valsartan
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg FMI tablet
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.11
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.22

    Primary: Adjusted Geometric mean of Cmax for comparison of mini-tablets and FMI tablets for LCZ696 – Completers

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    End point title
    		 Adjusted Geometric mean of Cmax for comparison of mini-tablets and FMI tablets for LCZ696 – Completers
    End point description
    Cmax measures the observed maximum plasma concentration following drug administration [ng/mL].
    End point type
    Primary
    End point timeframe
    Pre-dose (0 h) until 96 h postdose. Additional outpatient PK blood sampling at 48, 72, and 96 h postdose.
    End point values
    		 LCZ696 200 mg mini-tablets LCZ696 200 mg FMI tablet
    Number of subjects analysed
    40 [5]
    40 [6]
    Units: ng/mL
    number (not applicable)
        Analyte AHU377
    1623
    1721
        Analyte LBQ657
    7374
    7771
        Analyte Valsartan
    3767
    3459
    Notes
    [5] - PK analysis set
    [6] - PK analysis set
    Statistical analysis title
    		 Comparison result - Cmax AHU377
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg FMI tablet
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.94
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.11
    Statistical analysis title
    		 Comparison result - Cmax LBQ657
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg FMI tablet
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.95
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 0.99
    Statistical analysis title
    		 Comparison result - Cmax Valsartan
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg FMI tablet
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.09
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.21

    Primary: Adjusted Geometric mean of AUCinf for comparison for mini-tablets with pudding and Mini-tablets for LCZ696 – Completers

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    End point title
    		 Adjusted Geometric mean of AUCinf for comparison for mini-tablets with pudding and Mini-tablets for LCZ696 – Completers
    End point description
    AUCinf measures the area under the plasma concentration-time curve from time zero to infinity [ng*h/mL].
    End point type
    Primary
    End point timeframe
    Pre-dose (0 h) until 96 h postdose. Additional outpatient PK blood sampling at 48, 72, and 96 h postdose.
    End point values
    		 LCZ696 200 mg mini-tablets LCZ696 200 mg mini-tablets with pudding
    Number of subjects analysed
    40 [7]
    40 [8]
    Units: ng*h/mL
    number (not applicable)
        Analyte AHU377
    1930
    2005
        Analyte LBQ657
    79831
    80421
        Analyte Valsartan
    21226
    21598
    Notes
    [7] - PK analysis set n= 39, 39, 38
    [8] - PK analysis set n= 39, 39, 38
    Statistical analysis title
    		 Comparison result - AUCinf AHU377
    Comparison groups
    LCZ696 200 mg mini-tablets with pudding v LCZ696 200 mg mini-tablets
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.08
    Statistical analysis title
    		 Comparison result - AUCinf LBQ657
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg mini-tablets with pudding
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.03
    Statistical analysis title
    		 Comparison result - AUCinf Valsartan
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg mini-tablets with pudding
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.11

    Primary: Adjusted Geometric mean of AUClast for comparison for mini-tablets with pudding and Mini-tablets for LCZ696 – Completers

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    End point title
    		 Adjusted Geometric mean of AUClast for comparison for mini-tablets with pudding and Mini-tablets for LCZ696 – Completers
    End point description
    AUClast measures the area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration [ng*h/mL].
    End point type
    Primary
    End point timeframe
    Pre-dose (0 h) until 96 h postdose. Additional outpatient PK blood sampling at 48, 72, and 96 h postdose.
    End point values
    		 LCZ696 200 mg mini-tablets LCZ696 200 mg mini-tablets with pudding
    Number of subjects analysed
    39 [9]
    39 [10]
    Units: ng*h/mL
    number (not applicable)
        Analyte AHU377
    1926
    2001
        Analyte LBQ657
    79175
    79731
        Analyte Valsartan
    20598
    21343
    Notes
    [9] - PK analysis set
    [10] - PK analysis set
    Statistical analysis title
    		 Comparison result - AUClast AHU377
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg mini-tablets with pudding
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.08
    Statistical analysis title
    		 Comparison result - AUClast LBQ657
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg mini-tablets with pudding
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.03
    Statistical analysis title
    		 Comparison result - AUClast Valsartan
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg mini-tablets with pudding
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.14

    Primary: Adjusted Geometric mean of Cmax for comparison for mini-tablets with pudding and Mini-tablets for LCZ696 – Completers

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    End point title
    		 Adjusted Geometric mean of Cmax for comparison for mini-tablets with pudding and Mini-tablets for LCZ696 – Completers
    End point description
    Cmax measures the observed maximum plasma concentration following drug administration [ng/mL].
    End point type
    Primary
    End point timeframe
    Pre-dose (0 h) until 96 h postdose. Additional outpatient PK blood sampling at 48, 72, and 96 h postdose.
    End point values
    		 LCZ696 200 mg mini-tablets LCZ696 200 mg mini-tablets with pudding
    Number of subjects analysed
    39 [11]
    39 [12]
    Units: ng/mL
    number (not applicable)
        Analyte AHU377
    1629
    1627
        Analyte LBQ657
    7373
    7279
        Analyte Valsartan
    3720
    3792
    Notes
    [11] - PK analysis set
    [12] - PK analysis set
    Statistical analysis title
    		 Comparison result - Cmax AHU377
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg mini-tablets with pudding
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.18
    Statistical analysis title
    		 Comparison result - Cmax LBQ657
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg mini-tablets with pudding
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.99
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.03
    Statistical analysis title
    		 Comparison result - Cmax Valsartan
    Comparison groups
    LCZ696 200 mg mini-tablets v LCZ696 200 mg mini-tablets with pudding
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.13

    Primary: Adjusted Geometric mean of AUCinf for comparison for mini-tablets with pudding and Mini-tablets with pudding and high fat meal for LCZ696 – Completers

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    End point title
    		 Adjusted Geometric mean of AUCinf for comparison for mini-tablets with pudding and Mini-tablets with pudding and high fat meal for LCZ696 – Completers
    End point description
    AUCinf measures the area under the plasma concentration-time curve from time zero to infinity [ng*h/mL].
    End point type
    Primary
    End point timeframe
    Pre-dose (0 h) until 96 h postdose. Additional outpatient PK blood sampling at 48, 72, and 96 h postdose.
    End point values
    		 LCZ696 200 mg mini-tablets with pudding LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects analysed
    40 [13]
    40 [14]
    Units: ng*h/mL
    number (not applicable)
        Analyte AHU377
    1992
    2008
        Analyte LBQ657
    80425
    81983
        Analyte Valsartan
    21878
    13032
    Notes
    [13] - PK analysis set n= 38, 39, 35
    [14] - PK analysis set n= 38, 39, 35
    Statistical analysis title
    		 Comparison result - AUCinf AHU377
    Comparison groups
    LCZ696 200 mg mini-tablets with pudding v LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.05
    Statistical analysis title
    		 Comparison result - AUCinf LBQ657
    Comparison groups
    LCZ696 200 mg mini-tablets with pudding v LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.04
    Statistical analysis title
    		 Comparison result - AUCinf Valsartan
    Comparison groups
    LCZ696 200 mg mini-tablets with pudding v LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.66

    Primary: Adjusted Geometric mean of AUClast for comparison for mini-tablets with pudding and Mini-tablets with pudding and high fat meal for LCZ696 – Completers

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    End point title
    		 Adjusted Geometric mean of AUClast for comparison for mini-tablets with pudding and Mini-tablets with pudding and high fat meal for LCZ696 – Completers
    End point description
    AUClast measures the area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration [ng*h/mL].
    End point type
    Primary
    End point timeframe
    Pre-dose (0 h) until 96 h postdose. Additional outpatient PK blood sampling at 48, 72, and 96 h postdose.
    End point values
    		 LCZ696 200 mg mini-tablets with pudding LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects analysed
    39 [15]
    39 [16]
    Units: ng*h/mL
    number (not applicable)
        Analyte AHU377
    2001
    2000
        Analyte LBQ657
    79734
    81332
        Analyte Valsartan
    21376
    12653
    Notes
    [15] - PK analysis set
    [16] - PK analysis set
    Statistical analysis title
    		 Comparison result - AUClast AHU377
    Comparison groups
    LCZ696 200 mg mini-tablets with pudding and high fat meal v LCZ696 200 mg mini-tablets with pudding
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.04
    Statistical analysis title
    		 Comparison result - AUClast LBQ657
    Comparison groups
    LCZ696 200 mg mini-tablets with pudding v LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.04
    Statistical analysis title
    		 Comparison result - AUClast Valsartan
    Comparison groups
    LCZ696 200 mg mini-tablets with pudding v LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.59
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.65

    Primary: Adjusted Geometric mean of Cmax for comparison for mini-tablets with pudding and Mini-tablets with pudding and high fat meal for LCZ696 – Completers

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    End point title
    		 Adjusted Geometric mean of Cmax for comparison for mini-tablets with pudding and Mini-tablets with pudding and high fat meal for LCZ696 – Completers
    End point description
    Cmax measures the observed maximum plasma concentration following drug administration [ng/mL].
    End point type
    Primary
    End point timeframe
    Pre-dose (0 h) until 96 h postdose. Additional outpatient PK blood sampling at 48, 72, and 96 h postdose.
    End point values
    		 LCZ696 200 mg mini-tablets with pudding LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects analysed
    39 [17]
    39 [18]
    Units: ng/mL
    number (not applicable)
        Analyte AHU377
    1628
    650
        Analyte LBQ657
    7279
    5872
        Analyte Valsartan
    3797
    1617
    Notes
    [17] - PK analysis set
    [18] - PK analysis set
    Statistical analysis title
    		 Comparison result - Cmax AHU377
    Comparison groups
    LCZ696 200 mg mini-tablets with pudding v LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.46
    Statistical analysis title
    		 Comparison result - Cmax LBQ657
    Comparison groups
    LCZ696 200 mg mini-tablets with pudding v LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.81
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 0.85
    Statistical analysis title
    		 Comparison result - Cmax Valsartan
    Comparison groups
    LCZ696 200 mg mini-tablets with pudding v LCZ696 200 mg mini-tablets with pudding and high fat meal
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.43
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.48

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    LCZ696 200 mg FMI tablet
    Reporting group description
    		 LCZ696 200 mg FMI tablet

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    LCZ696 200 mg mini-tablets with pudding
    Reporting group description
    		 LCZ696 200 mg mini-tablets with pudding

    Serious adverse events
    		 LCZ696 200 mg FMI tablet Total LCZ696 200 mg mini-tablets with pudding
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 LCZ696 200 mg FMI tablet Total LCZ696 200 mg mini-tablets with pudding
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 40 (10.00%)
    3 / 39 (7.69%)
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Vessel puncture site pain
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    1
    Vessel puncture site swelling
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
         occurrences all number
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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