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    Clinical Trial Results:
    A randomized, 8-week, double-blind, parallel-group, activecontrolled, multi-center study to evaluate the efficacy and safety of LCZ696 200 mg in comparison with olmesartan 20 mg in patients with essential hypertension not adequately responsive to olmesartan 20 mg treatment

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2013-001783-36
    Trial protocol
    		 ES  
    Global end of trial date
    14 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 May 2016
    First version publication date
    20 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCZ696A2318
    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)
    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
    14 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of LCZ696 200 mg compared to olmesartan 20 mg in patients with essential hypertension that do not have a satisfactory response to olmesartan 20 mg by testing the hypothesis of superior reduction in mean 24-hour ambulatory systolic blood pressure (maSBP) after 8 weeks of treatment
    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
    09 Sep 2013
    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: 62
    Country: Number of subjects enrolled
    Spain: 38
    Country: Number of subjects enrolled
    Guatemala: 21
    Country: Number of subjects enrolled
    Philippines: 40
    Country: Number of subjects enrolled
    Russian Federation: 42
    Country: Number of subjects enrolled
    United States: 172
    Worldwide total number of subjects
    375
    EEA total number of subjects
    38
    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)
    287
    From 65 to 84 years
    87
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Randomized 376 patients but one was incorrectly randomized to the olmesartan 20 mg treatment but did not receive any double-blind medication, and hence was excluded from analysis sets.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LCZ696 200 mg
    Arm description
    		 Patients will be treated with one LCZ696 200 mg tablet and one placebo of olmesartan 20 mg capsule once daily for 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    sacubitril/valsartan
    Investigational medicinal product code
    LCZ696
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LCZ696 200 mg

    Arm title
    		 Olmesartan 20 mg
    Arm description
    		 Patients will be treated with one placebo of LCZ696 200 mg tablet and one olmesartan 20 mg capsule once daily for 8 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Olmesartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Olmesartan 20 mg

    Number of subjects in period 1
    		LCZ696 200 mg Olmesartan 20 mg
    Started
    188
    187
    Full analysis set (FAS)
    188
    187
    Safety set (SAF)
    188
    187
    Completed
    179
    175
    Not completed
    9
    12
         Physician decision
    -
    2
         Adverse event, non-fatal
    2
    5
         Protocol deviation
    3
    2
         Non-compliance
    -
    1
         Lost to follow-up
    -
    1
         Subject/guardian decision
    3
    1
         Lack of efficacy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LCZ696 200 mg
    Reporting group description
    		 Patients will be treated with one LCZ696 200 mg tablet and one placebo of olmesartan 20 mg capsule once daily for 8 weeks.

    Reporting group title
    Olmesartan 20 mg
    Reporting group description
    		 Patients will be treated with one placebo of LCZ696 200 mg tablet and one olmesartan 20 mg capsule once daily for 8 weeks.

    Reporting group values
    		 LCZ696 200 mg Olmesartan 20 mg Total
    Number of subjects
    		 188 187 375
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 144 143 287
        From 65-84 years
    		 43 44 87
        85 years and over
    		 1 0 1
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 57.1 ( 10.19 ) 58 ( 9.09 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 91 92 183
        Male
    		 97 95 192

    End points

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    End points reporting groups
    Reporting group title
    LCZ696 200 mg
    Reporting group description
    		 Patients will be treated with one LCZ696 200 mg tablet and one placebo of olmesartan 20 mg capsule once daily for 8 weeks.

    Reporting group title
    Olmesartan 20 mg
    Reporting group description
    		 Patients will be treated with one placebo of LCZ696 200 mg tablet and one olmesartan 20 mg capsule once daily for 8 weeks.

    Primary: Change from baseline in 24-hour mean ambulatory systolic blood pressure (maSBP)

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    End point title
    		 Change from baseline in 24-hour mean ambulatory systolic blood pressure (maSBP)
    End point description
    Twenty-four hour mean ambulatory blood pressure measurements (ABPM) will be performed at baseline and at end of study (week 8). The first 24-hour ABPM will be performed beginning at 24 hours prior to baseline visit and the second will be performed 24 hours prior to week 8 visit.
    End point type
    Primary
    End point timeframe
    baseline, 8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    167
    164
    Units: mmHg
        least squares mean (standard error)
    -4.26 ( 0.6 )
    -1.04 ( 0.61 )
    Statistical analysis title
    		 Change from baseline in 24-hour (maSBP)
    Comparison groups
    LCZ696 200 mg v Olmesartan 20 mg
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.73
         upper limit
    		 -1.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.78

    Secondary: Change from baseline in mean 24-hour ambulatory diastolic blood pressure (maDBP)

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    End point title
    		 Change from baseline in mean 24-hour ambulatory diastolic blood pressure (maDBP)
    End point description
    Twenty-four hour mean ambulatory blood pressure measurements (ABPM) will be performed at baseline and at end of study (week 8). The 24-hour ABPM measurements are performed beginning 24 hours prior to baseline and week 8 visits.
    End point type
    Secondary
    End point timeframe
    baseline, 8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    167
    164
    Units: mmHg
        least squares mean (standard error)
    -2.27 ( 0.39 )
    -0.35 ( 0.39 )
    No statistical analyses for this end point

    Secondary: Change from baseline in mean sitting systolic blood pressure (msSBP)

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    End point title
    		 Change from baseline in mean sitting systolic blood pressure (msSBP)
    End point description
    Sitting blood pressure (BP) measurement will be taken at every visit from screening through end of study. For each participant at each visit, four separate sitting BP measurements will be obtained (with a full two minute interval between measurements) and averaged to obtain the mean
    End point type
    Secondary
    End point timeframe
    baseline, 8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    188
    187
    Units: mmHg
        least squares mean (standard error)
    -14.21 ( 1.28 )
    -10.03 ( 1.29 )
    No statistical analyses for this end point

    Secondary: Change from baseline in mean sitting diastolic blood pressure (msDBP)

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    End point title
    		 Change from baseline in mean sitting diastolic blood pressure (msDBP)
    End point description
    Sitting blood pressure (BP) measurement will be taken at every visit from screening through end of study. For each participant at each visit, four separate sitting BP measurements will be obtained (with a full two minute interval between measurements) and averaged to obtain the mean
    End point type
    Secondary
    End point timeframe
    baseline, 8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    188
    187
    Units: mmHg
        least squares mean (standard error)
    -7.52 ( 0.7 )
    -4.47 ( 0.71 )
    No statistical analyses for this end point

    Secondary: Change from baseline in office pulse pressure

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    End point title
    		 Change from baseline in office pulse pressure
    End point description
    Mean sitting pulse pressure (msPP) will be calculated at screening through end of study at every visit. Mean sitting pulse pressure is calculated as msSBP-msDBP.
    End point type
    Secondary
    End point timeframe
    baseline, 8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    188
    187
    Units: mmHg
        least squares mean (standard error)
    -6.67 ( 0.94 )
    -5.54 ( 0.94 )
    No statistical analyses for this end point

    Secondary: Number of patients achieving successful overall blood pressure control

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    End point title
    		 Number of patients achieving successful overall blood pressure control
    End point description
    Successful overall blood pressure control is defined as both msSBP/msDBP <140/90 mmHg
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    188
    187
    Units: Participants
    76
    52
    No statistical analyses for this end point

    Secondary: Number of patients achieving successful mean sitting systolic blood pressure (msSBP) control

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    End point title
    		 Number of patients achieving successful mean sitting systolic blood pressure (msSBP) control
    End point description
    Successful mean sitting systolic blood pressure control is defined as msSBP <140 mmHg
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    188
    187
    Units: Participants
    84
    58
    No statistical analyses for this end point

    Secondary: Number of patients achieving successful mean sitting diastolic blood pressure (msDBP) control

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    End point title
    		 Number of patients achieving successful mean sitting diastolic blood pressure (msDBP) control
    End point description
    Successful mean sitting diastolic blood pressure control is defined as msDBP <90 mmHg or reduction >=10 mmHg
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    188
    187
    Units: Participants
    133
    112
    No statistical analyses for this end point

    Secondary: Number of patients achieving successful mean sitting systolic blood pressure (msSBP) response

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    End point title
    		 Number of patients achieving successful mean sitting systolic blood pressure (msSBP) response
    End point description
    Successful mean sitting systolic blood pressure response is defined as msSBP <140 mmHg or a reduction ≥ 20 mmHg from baseline.
    End point type
    Secondary
    End point timeframe
    baseline, 8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    188
    187
    Units: Participants
    90
    65
    No statistical analyses for this end point

    Secondary: Number of patients achieving successful mean sitting diastolic blood pressure (msDBP) response

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    End point title
    		 Number of patients achieving successful mean sitting diastolic blood pressure (msDBP) response
    End point description
    Successful mean sitting diastolic blood pressure response is defined as msDBP <90 mmHg or a reduction ≥10 mmHg from baseline.
    End point type
    Secondary
    End point timeframe
    baseline, 8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    188
    187
    Units: Participants
    137
    115
    No statistical analyses for this end point

    Secondary: Number of patients with total adverse events, serious adverse events and death

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    End point title
    		 Number of patients with total adverse events, serious adverse events and death
    End point description
    Number of patients with total adverse events, serious adverse events and death were reported.
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 LCZ696 200 mg Olmesartan 20 mg
    Number of subjects analysed
    188
    187
    Units: Number of participants
        Adverse events (serious and non-serious)
    44
    41
        Serious Adverse Events
    0
    2
        Deaths
    0
    0
    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
    17.0
    Reporting groups
    Reporting group title
    LCZ696 200 mg
    Reporting group description
    		 LCZ696 200 mg

    Reporting group title
    OLMESARTAN 20 mg
    Reporting group description
    		 OLMESARTAN 20 mg

    Serious adverse events
    		 LCZ696 200 mg OLMESARTAN 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 188 (0.00%)
    2 / 187 (1.07%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BENIGN NEOPLASM OF THYROID GLAND
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 LCZ696 200 mg OLMESARTAN 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 188 (3.72%)
    10 / 187 (5.35%)
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    5 / 188 (2.66%)
    6 / 187 (3.21%)
         occurrences all number
    5
    6
    DIZZINESS
         subjects affected / exposed
    2 / 188 (1.06%)
    4 / 187 (2.14%)
         occurrences all number
    2
    4

    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
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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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