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    Clinical Trial Results:
    A randomized, double-blind, active-controlled, parallel group, 52-week study to evaluate the effect of LCZ696 compared to olmesartan on regional aortic stiffness in subjects with essential hypertension

    Summary
    EudraCT number
    		 2012-005720-15
    Trial protocol
    		 GB   DE  
    Global end of trial date
    04 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jun 2016
    First version publication date
    17 Jun 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLCZ696A2224
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01870739
    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
    04 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of LCZ696 based treatment regimen as compared to olmesartan on local aortic distensibility as measured by MRI after 52 weeks of treatment in hypertensive patients
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Oct 2013
    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
    Germany: 91
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Switzerland: 21
    Worldwide total number of subjects
    114
    EEA total number of subjects
    93
    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)
    76
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 115 patients were enrolled. One patient was discontinued after randomization before receiving any dose of study randomized medication. A total of 114 patients received study randomized medication

    Period 1
    Period 1 title
    Single Drug treatment (12 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 sacubitril/valsartan (LCZ696)
    Arm description
    		 LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
    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
    200 mg tablets

    Investigational medicinal product name
    Amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg, 5 mg, and 10 mg once daily

    Investigational medicinal product name
    placebo of olmesartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    matching placebo of olmesartan

    Arm title
    		 olmesartan
    Arm description
    		 Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
    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 capsule

    Investigational medicinal product name
    Amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg, 5 mg, and 10 mg once daily

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

    Number of subjects in period 1
    		sacubitril/valsartan (LCZ696) olmesartan
    Started
    57
    57
    Initiation Dose completed
    57
    56
    Maintenance Dose started
    57
    56
    Completed
    54
    53
    Not completed
    3
    4
         Adverse event, non-fatal
    -
    1
         Protocol deviation
    -
    1
         Administrative problems
    3
    2
    Period 2
    Period 2 title
    Add-on Period (40 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 sacubitril/valsartan (LCZ696)
    Arm description
    		 LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
    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
    200 mg tablets

    Investigational medicinal product name
    Amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg, 5 mg, and 10 mg once daily

    Investigational medicinal product name
    placebo of olmesartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    matching placebo of olmesartan

    Arm title
    		 olmesartan
    Arm description
    		 Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
    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 capsule

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

    Investigational medicinal product name
    Amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg, 5 mg, and 10 mg once daily

    Number of subjects in period 2
    		sacubitril/valsartan (LCZ696) olmesartan
    Started
    54
    53
    Completed
    51
    51
    Not completed
    3
    2
         Patient withdrew consent
    1
    -
         Adverse event, non-fatal
    -
    1
         Unsatisfactory therapeutic effect
    1
    -
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    sacubitril/valsartan (LCZ696)
    Reporting group description
    		 LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)

    Reporting group title
    olmesartan
    Reporting group description
    		 Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)

    Reporting group values
    		 sacubitril/valsartan (LCZ696) olmesartan Total
    Number of subjects
    		 57 57 114
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 60.5 ( 7.8 ) 59.2 ( 13.1 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 20 17 37
        Male
    		 37 40 77

    End points

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    End points reporting groups
    Reporting group title
    sacubitril/valsartan (LCZ696)
    Reporting group description
    		 LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)

    Reporting group title
    olmesartan
    Reporting group description
    		 Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
    Reporting group title
    sacubitril/valsartan (LCZ696)
    Reporting group description
    		 LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)

    Reporting group title
    olmesartan
    Reporting group description
    		 Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)

    Subject analysis set title
    Initiation dose : sacubitril/valsartan (LCZ696 200mg)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients received LCZ696 200 mg for 2 weeks as initiation dose for 2 weeks

    Subject analysis set title
    Initiation dose: olmesartan 20mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients received olmesartan 20 mg for 2 weeks as initiation dose for 2 weeks

    Subject analysis set title
    Maintenance Dose: sacubitril/valsartan (LCZ696 400mg)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    After 2 weeks on initiation dose, patients were dosed at the maintenance dose level of LCZ696 400 mg for 10 weeks

    Subject analysis set title
    Maintenance Dose: olmesartan 40 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    After 2 weeks on initiation dose, patients were dosed at the maintenance dose level of olmesartan 40 mg for 10 weeks

    Subject analysis set title
    Sacubitril/valsartan (LCZ696 400mg) +/- Amlodipine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target

    Subject analysis set title
    Olmesartan 40mg +/- Amlodipine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target

    Primary: Change from baseline in ascending aorta distensibility at 52 week

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    End point title
    		 Change from baseline in ascending aorta distensibility at 52 week
    End point description
    Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Ascending aorta distensibility was one of the 3 components for measuring local arota distensibility.
    End point type
    Primary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 sacubitril/valsartan (LCZ696) olmesartan
    Number of subjects analysed
    49
    53
    Units: 10^(-3) x mmHg^(-1)
        least squares mean (standard error)
    0.269 ( 0.1283 )
    0.33 ( 0.1233 )
    Statistical analysis title
    		 Treatment diff. in Ascending Aorta Distensibility
    Comparison groups
    sacubitril/valsartan (LCZ696) v olmesartan
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7324
    Method
    		 Linear Model
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.0616
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4178
         upper limit
    		 0.2947

    Primary: Change from baseline in proximal descending aorta distensibility at 52 weeks

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    End point title
    		 Change from baseline in proximal descending aorta distensibility at 52 weeks
    End point description
    Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Proximal descending aorta distensibility was one of the 3 components for measuring local arota distensibility.
    End point type
    Primary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 sacubitril/valsartan (LCZ696) olmesartan
    Number of subjects analysed
    49
    53
    Units: 10^(-3) x mmHg^(-1)
        least squares mean (standard error)
    0.51 ( 0.1528 )
    0.547 ( 0.1469 )
    Statistical analysis title
    		 Treatment diff. in Proximal Descending Aorta
    Comparison groups
    sacubitril/valsartan (LCZ696) v olmesartan
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8614
    Method
    		 Linear Model
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.0371
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4582
         upper limit
    		 0.3839

    Primary: Change from baseline in distal descending aorta distensibility at 52 weeks

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    End point title
    		 Change from baseline in distal descending aorta distensibility at 52 weeks
    End point description
    Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Distal descending aorta distensibility was one of the 3 components for measuring local arota distensibility.
    End point type
    Primary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 sacubitril/valsartan (LCZ696) olmesartan
    Number of subjects analysed
    49
    53
    Units: 10^(-3) x mmHg^(-1)
        least squares mean (standard error)
    0.417 ( 0.2242 )
    0.498 ( 0.2156 )
    Statistical analysis title
    		 Treatment diff. in distal descending aorta
    Comparison groups
    sacubitril/valsartan (LCZ696) v olmesartan
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7946
    Method
    		 Linear Model
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.0812
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6987
         upper limit
    		 0.5362

    Secondary: Change from baseline in local aortic strain at 52 weeks

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    End point title
    		 Change from baseline in local aortic strain at 52 weeks
    End point description
    Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic strain. Local aortic strain was measured by assessing ascending aorta strain, proximal descending aorta strain and distal descending aorta strain.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 sacubitril/valsartan (LCZ696) olmesartan
    Number of subjects analysed
    49
    53
    Units: percentage of change in aorta strain
    least squares mean (standard error)
        Ascending Aorta Strain
    -0.83 ( 0.7903 )
    0.453 ( 0.7598 )
        Proximal Descending Aorta Strain
    -0.284 ( 0.894 )
    -0.066 ( 0.8596 )
        Distal Descending Aorta Strain
    -1.092 ( 1.0956 )
    0.225 ( 1.0533 )
    No statistical analyses for this end point

    Secondary: Change from baseline in regional aortic pulse wave velocity at 52 weeks

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    End point title
    		 Change from baseline in regional aortic pulse wave velocity at 52 weeks
    End point description
    Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of regional aortic pulse wave velocity.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 sacubitril/valsartan (LCZ696) olmesartan
    Number of subjects analysed
    49
    53
    Units: meters per second (m/s)
        least squares mean (standard error)
    -2.086 ( 0.5029 )
    -1.085 ( 0.4835 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Central blood pressure at 52 weeks

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    End point title
    		 Change from baseline in Central blood pressure at 52 weeks
    End point description
    Central blood pressure was determined by measuring central systolic blood pressure , diastolic blood pressure and pulse pressure.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 sacubitril/valsartan (LCZ696) olmesartan
    Number of subjects analysed
    50
    50
    Units: mmHg
    least squares mean (standard error)
        Central systolic blood pressure
    -16.655 ( 1.4968 )
    -13.625 ( 1.4968 )
        Central diastolic blood pressure
    -10.318 ( 1.0578 )
    -10.432 ( 1.0578 )
        Central pulse pressure
    -6.539 ( 0.9428 )
    -3.041 ( 0.9428 )
    No statistical analyses for this end point

    Secondary: Change from baseline in augmentation pressure at 52 weeks

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    End point title
    		 Change from baseline in augmentation pressure at 52 weeks
    End point description
    Augmentation pressure is the added pressure during systole due to wave reflection.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 sacubitril/valsartan (LCZ696) olmesartan
    Number of subjects analysed
    50
    50
    Units: mmHg
        least squares mean (standard error)
    -2.443 ( 0.595 )
    -1.437 ( 0.595 )
    No statistical analyses for this end point

    Secondary: Change from baseline in augmentation index at 52 weeks

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    End point title
    		 Change from baseline in augmentation index at 52 weeks
    End point description
    Augmentation index (Alx) is the percentage of the central pulse pressure due to wave reflection.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 sacubitril/valsartan (LCZ696) olmesartan
    Number of subjects analysed
    50
    50
    Units: percentage of change in Alx
        least squares mean (standard error)
    -2.385 ( 1.1805 )
    -1.515 ( 1.1805 )
    No statistical analyses for this end point

    Secondary: Change from baseline in carotid-femoral pulse wave velocity at 52 weeks

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    End point title
    		 Change from baseline in carotid-femoral pulse wave velocity at 52 weeks
    End point description
    For pulse wave velocity calculation, the pressure waveform at the femoral site (using a partially inflated custom blood pressure cuff) and the carotid site (using hand -held applanation tonometry) were measured simultaneously. Pulse wave analysis was performed on the central aortic pressure waveform as derived from the brachial pressure waveform recorded in a partially-inflated blood pressure cuff around the upper arm.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 sacubitril/valsartan (LCZ696) olmesartan
    Number of subjects analysed
    50
    50
    Units: meters per second (m/s)
        least squares mean (standard error)
    -0.428 ( 0.1663 )
    -0.434 ( 0.1663 )
    No statistical analyses for this end point

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

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    End point title
    		 Number of patients with reported adverse events, serious adverse events and death
    End point description
    This outcome measure summarizes patients with any adverse events, serious adverse events and death.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Initiation dose : sacubitril/valsartan (LCZ696 200mg) Initiation dose: olmesartan 20mg Maintenance Dose: sacubitril/valsartan (LCZ696 400mg) Maintenance Dose: olmesartan 40 mg Sacubitril/valsartan (LCZ696 400mg) +/- Amlodipine Olmesartan 40mg +/- Amlodipine
    Number of subjects analysed
    57
    57
    57
    56
    54
    53
    Units: Patients
        Any Adverse events
    13
    16
    21
    28
    31
    38
        Serious Adverse Events
    0
    2
    0
    2
    6
    5
        Death
    0
    0
    0
    0
    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 are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Initiation dose : sacubitril/valsartan (LCZ696 200mg)
    Reporting group description
    		 Patients received LCZ696 200 mg for 2 weeks as initiation dose for 2 weeks

    Reporting group title
    Initiation dose: olmesartan 20mg
    Reporting group description
    		 Patients received olmesartan 20 mg for 2 weeks as initiation dose for 2 weeks

    Reporting group title
    Maintenance Dose: sacubitril/valsartan (LCZ696 400mg)
    Reporting group description
    		 After 2 weeks on initiation dose, patients were dosed at the maintenance dose level of LCZ696 400 mg for 10 weeks

    Reporting group title
    Maintenance Dose: olmesartan 40 mg
    Reporting group description
    		 After 2 weeks on initiation dose, patients were dosed at the maintenance dose level of olmesartan 40 mg for 10 weeks

    Reporting group title
    Sacubitril/valsartan (LCZ696 400mg) +/- Amlodipine
    Reporting group description
    		 Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target

    Reporting group title
    Olmesartan 40mg +/- Amlodipine
    Reporting group description
    		 Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target

    Serious adverse events
    		 Initiation dose : sacubitril/valsartan (LCZ696 200mg) Initiation dose: olmesartan 20mg Maintenance Dose: sacubitril/valsartan (LCZ696 400mg) Maintenance Dose: olmesartan 40 mg Sacubitril/valsartan (LCZ696 400mg) +/- Amlodipine Olmesartan 40mg +/- Amlodipine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
    0 / 57 (0.00%)
    2 / 56 (3.57%)
    6 / 54 (11.11%)
    5 / 53 (9.43%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Fall
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    General disorders and administration site conditions
    Fat necrosis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nodule
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterocolitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Initiation dose : sacubitril/valsartan (LCZ696 200mg) Initiation dose: olmesartan 20mg Maintenance Dose: sacubitril/valsartan (LCZ696 400mg) Maintenance Dose: olmesartan 40 mg Sacubitril/valsartan (LCZ696 400mg) +/- Amlodipine Olmesartan 40mg +/- Amlodipine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 57 (5.26%)
    6 / 57 (10.53%)
    10 / 57 (17.54%)
    14 / 56 (25.00%)
    16 / 54 (29.63%)
    24 / 53 (45.28%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
    2 / 57 (3.51%)
    6 / 56 (10.71%)
    2 / 54 (3.70%)
    2 / 53 (3.77%)
         occurrences all number
    0
    2
    3
    6
    10
    5
    Dizziness
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 57 (3.51%)
    4 / 57 (7.02%)
    1 / 56 (1.79%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences all number
    1
    2
    4
    1
    1
    0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    4 / 53 (7.55%)
         occurrences all number
    0
    0
    1
    0
    1
    4
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    2 / 56 (3.57%)
    3 / 54 (5.56%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    2
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    Back pain
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    5 / 56 (8.93%)
    1 / 54 (1.85%)
    5 / 53 (9.43%)
         occurrences all number
    1
    0
    0
    5
    2
    6
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
    4 / 57 (7.02%)
    5 / 56 (8.93%)
    11 / 54 (20.37%)
    10 / 53 (18.87%)
         occurrences all number
    0
    2
    5
    5
    14
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Nov 2013
    The reason for this protocol amendment was a change in the recommended BP targets for patients with diabetes or chronic kidney disease as laid out in the most recent ESC guidance. The new ESC guidance was issued after the original release date of this study protocol. The second change relates to clarification of the amlodipine dosing regimen. The selection of the starting dose was up to the discretion of the investigator to allow for individualized treatment and utilization of the different approved doses of amlodipine in the different countries. Finally, the background section and benefit-risk assessment were updated to describe the observation in a non-human primate study of an increase in amyloid beta in the cerebrospinal fluid when treated with LCZ696 for 2 weeks. This finding was reported to health authorities, ethics committees and investigators separately.
    18 Jun 2014
    The reason for this protocol amendment was to update the protocol with the latest safety information regarding the increase in CSF amyloid beta that was observed in monkeys.A study in humans has concluded that this effect was not reproduced in humans. Another reason for this protocol amendment was to change the timing of assessment of the study’s primary and secondary objectives from 12 weeks to 52 weeks (12 months). An interim analysis (IA) was initially planned when approximately 128 evaluable patients completed the 12 week assessments. With the change from 12 to 52 weeks in the timing of the primary and secondary endpoints, the week 12 IA was no longer needed. Hence the 12 week IA was removed.

    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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