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    Clinical Trial Results:
    A randomized, double-blind, parallel group study to evaluate metabolic effects of LCZ696 and amlodipine in obese hypertensive subjects

    Summary
    EudraCT number
    		 2012-002606-40
    Trial protocol
    		 DE   NL  
    Global end of trial date
    29 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    18 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCZ696B2207
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01631864
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jul 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of LCZ696 400 mg QD as compared to amlodipine 10 mg QD on insulin sensitivity after 8 weeks of treatment in obese hypertensive 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
    23 Oct 2012
    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
    Netherlands: 27
    Country: Number of subjects enrolled
    Germany: 71
    Worldwide total number of subjects
    98
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    91
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 After signing the Informed Consent, patients underwent screening assessments. If eligibility criteria were met, patients proceeded to the wash-out period (wash-out from previous anti-hypertensive medication).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LCZ696
    Arm description
    		 LCZ696 400 mg + placebo to amlodipine 10 mg (2 x placebo to matching amlodipine 5 mg)
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCZ696
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received LCZ696 400 mg tablets for oral administration for 56 days.

    Investigational medicinal product name
    Matching placebo for amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received matching placebo 10 mg (2 x placebo to matching amlodipine 5 mg) for 56 days.

    Arm title
    		 Amlodipine
    Arm description
    		 Patients received amlodipine 10 mg for 56 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Amlodipine 10 mg provided 5 mg tablets

    Investigational medicinal product name
    Matching placebo for LCZ696
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to LCZ696 400 mg

    Number of subjects in period 1
    		LCZ696 Amlodipine
    Started
    50
    48
    Completed
    48
    44
    Not completed
    2
    4
         Adverse event, non-fatal
    2
    3
         'Subject/guardian decision '
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696 400 mg + placebo to amlodipine 10 mg (2 x placebo to matching amlodipine 5 mg)

    Reporting group title
    Amlodipine
    Reporting group description
    		 Patients received amlodipine 10 mg for 56 days.

    Reporting group values
    		 LCZ696 Amlodipine Total
    Number of subjects
    		 50 48 98
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 47 44 91
        From 65-84 years
    		 3 4 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.9 ± 9.6 50.5 ± 9.4 -
    Gender categorical
    Units: Subjects
        Female
    		 9 13 22
        Male
    		 41 35 76

    End points

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    End points reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696 400 mg + placebo to amlodipine 10 mg (2 x placebo to matching amlodipine 5 mg)

    Reporting group title
    Amlodipine
    Reporting group description
    		 Patients received amlodipine 10 mg for 56 days.

    Primary: Change from baseline in insulin sensitivity index (SI) to Day 56

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    End point title
    		 Change from baseline in insulin sensitivity index (SI) to Day 56
    End point description
    The insulin sensitivity index was assessed by hyperinsulinemic euglycemic clamp. The insulin sensitivity index was calculated from steady-state glucose infusion rates, and blood insulin and glucose concentrations. The unit of measure is (μg/kg*min/(mmol/L*pmol/L)). The pharmacodynamic (PD) set was used for the analysis. The PD analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data.
    End point type
    Primary
    End point timeframe
    Baseline, Day 56
    End point values
    		 LCZ696 Amlodipine
    Number of subjects analysed
    48 [1]
    41 [2]
    Units: µg/kg*min/(mmol/L*pmol/L
    least squares mean (confidence interval 95%)
        Mean Change from baseline
    0.192 (0.025 to 0.359)
    0.065 (-0.116 to 0.246)
    Notes
    [1] - PD analysis set- Only patients who had both baseline and Day 56 values are included in the analysis
    [2] - PD analysis set- Only patients who had both baseline and Day 56 values are included in the analysis
    Statistical analysis title
    		 change from baseline-LCZ696 400mg-Amlodipine 10mg
    Statistical analysis description
    Comparison of change from baseline in insulin sensitivity index (SI) between treatments. Data were analyzed using an ANCOVA with treatment as fixed effect and baseline as covariate
    Comparison groups
    LCZ696 v Amlodipine
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 ANCOVA
    Point estimate
    0.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.119
         upper limit
    		 0.374

    Secondary: Subcutaneous adipose tissue lipolysis - Glycerol (free)

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    End point title
    		 Subcutaneous adipose tissue lipolysis - Glycerol (free)
    End point description
    Lipolysis was assessed through subcutaneous adipose tissue microdialysis in the fasted state before (Day 1) and at the end of the eight week treatment period (Day 57). Lipolysis was assessed during a 30 min and 45 min interval at rest. Pharmacodynamic set was included analysis.
    End point type
    Secondary
    End point timeframe
    After 8 weeks of treatment (Day 57)
    End point values
    		 LCZ696 Amlodipine
    Number of subjects analysed
    47
    42
    Units: µmol/L
    geometric mean (confidence interval 95%)
        30 minutes
    83.74 (75.35 to 94.61)
    67.89 (60.18 to 76.59)
        45 minutes
    80.53 (72.81 to 89.06)
    63.99 (57.52 to 71.2)
    No statistical analyses for this end point

    Secondary: oxidative metabolism as assessed by indirect calorimetry

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    End point title
    		 oxidative metabolism as assessed by indirect calorimetry
    End point description
    Oxidative metabolism at rest was assessed through measurement of oxygen consumption and carbon dioxide production (indirect calorimetry) at baseline and day 57.
    End point type
    Secondary
    End point timeframe
    Day 57
    End point values
    		 LCZ696 Amlodipine
    Number of subjects analysed
    46
    40
    Units: Carbon Dioxide to Oxygen Ratio
        arithmetic mean (confidence interval 95%)
    0.787 (0.76 to 0.814)
    0.775 (0.746 to 0.804)
    No statistical analyses for this end point

    Secondary: Percentage of patients that experienced at least one adverse event (AE)

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    End point title
    		 Percentage of patients that experienced at least one adverse event (AE)
    End point description
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 LCZ696 Amlodipine
    Number of subjects analysed
    50
    48
    Units: percentage of participants
        number (not applicable)
    60
    77.1
    No statistical analyses for this end point

    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
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Amlodipine 10mg QD
    Reporting group description
    		 Amlodipine 10mg QD

    Reporting group title
    LCZ696 400mg QD
    Reporting group description
    		 LCZ696 400mg QD

    Serious adverse events
    		 Amlodipine 10mg QD LCZ696 400mg QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 50 (2.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    RUPTURED CEREBRAL ANEURYSM
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Amlodipine 10mg QD LCZ696 400mg QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 48 (64.58%)
    24 / 50 (48.00%)
    Vascular disorders
    CIRCULATORY COLLAPSE
         subjects affected / exposed
    7 / 48 (14.58%)
    2 / 50 (4.00%)
         occurrences all number
    8
    2
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    HEADACHE
         subjects affected / exposed
    7 / 48 (14.58%)
    4 / 50 (8.00%)
         occurrences all number
    9
    4
    General disorders and administration site conditions
    OEDEMA PERIPHERAL
         subjects affected / exposed
    16 / 48 (33.33%)
    1 / 50 (2.00%)
         occurrences all number
    16
    1
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    Skin and subcutaneous tissue disorders
    PRURITUS
         subjects affected / exposed
    0 / 48 (0.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    5
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    8 / 48 (16.67%)
    9 / 50 (18.00%)
         occurrences all number
    9
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Sep 2012
    Added a clarification to the statistical analysis section as requested by the German ethical committee.

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

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

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