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    Clinical Trial Results:
    A randomized, double-blind 52-week study to evaluate the safety and efficacy of an LCZ696 regimen compared to an olmesartan regimen on arterial stiffness through assessment of central blood pressure in elderly patients with hypertension

    Summary
    EudraCT number
    		 2012-002899-14
    Trial protocol
    		 IT   GR   ES  
    Global end of trial date
    08 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Apr 2016
    First version publication date
    16 Apr 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLCZ696A2216
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01692301
    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, trialandresults.registries@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, trialandresults.registries@novartis.com
    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
    08 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate superiority of an LCZ696 regimen compared to an olmesartan regimen, as measured by change from baseline in mean CASP after 12 weeks of treatment in elderly patients with essential hypertension.
    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. Rescue medication (amlodipine or HCTZ) was allowed for patients whose BP was not controlled (msSBP ≥140 mmHg or msDBP ≥90 mmHg) after at least 8 weeks of treatment with LCZ696 400 mg or olmesartan 40 mg. Open-label amlodipine (2.5-5 mg) and then HCTZ (6.25-25 mg) was added at intervals of 4 weeks from Week 12 to Week 24.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Dec 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
    Argentina: 76
    Country: Number of subjects enrolled
    Colombia: 12
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Greece: 24
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 33
    Country: Number of subjects enrolled
    Russian Federation: 66
    Country: Number of subjects enrolled
    Spain: 58
    Country: Number of subjects enrolled
    Taiwan: 21
    Country: Number of subjects enrolled
    United States: 112
    Worldwide total number of subjects
    454
    EEA total number of subjects
    128
    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)
    154
    From 65 to 84 years
    296
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 454 patients were randomized to the 12-week double-blind epoch to receive LCZ696 or olmesartan

    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
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LCZ696 (sacubitril/valsartan)
    Arm description
    		 Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.
    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
    100 mg or 200 mg tablet

    Investigational medicinal product name
    Olmesartan matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Olmesartan matching placebo 20 mg and 40 mg capsules

    Investigational medicinal product name
    amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    amlodipine 2.5 mg or 5 mg tablets

    Investigational medicinal product name
    Hydrochlorothiazide
    Investigational medicinal product code
    HCTZ
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Hydrochlorothiazide 6.25mg, 12.5mg, or 25 mg tablets

    Arm title
    		 Olmesartan
    Arm description
    		 Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
    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
    20 mg and 40 mg capsules

    Investigational medicinal product name
    LCZ696 matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LCZ696 Matching Placebo of 100 mg or 200 mg tablet

    Investigational medicinal product name
    amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    amlodipine 2.5 mg or 5 mg tablets

    Investigational medicinal product name
    Hydrochlorothiazide
    Investigational medicinal product code
    HCTZ
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Hydrochlorothiazide 6.25mg, 12.5mg, or 25 mg tablets

    Number of subjects in period 1
    		LCZ696 (sacubitril/valsartan) Olmesartan
    Started
    229
    225
    Completed
    184
    183
    Not completed
    45
    42
         Adverse event, serious fatal
    1
    2
         Physician decision
    2
    2
         Adverse event, non-fatal
    15
    12
         Technical problems
    -
    1
         Non-compliance with study treatment
    1
    2
         Protocol deviation
    9
    2
         Patient/guardian decision
    16
    15
         Lost to follow-up
    1
    1
         Lack of efficacy
    -
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LCZ696 (sacubitril/valsartan)
    Reporting group description
    		 Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.

    Reporting group title
    Olmesartan
    Reporting group description
    		 Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.

    Reporting group values
    		 LCZ696 (sacubitril/valsartan) Olmesartan Total
    Number of subjects
    		 229 225 454
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 67 87 154
        From 65-84 years
    		 161 135 296
        85 years and over
    		 1 3 4
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 68.2 ( 5.73 ) 67.2 ( 5.97 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 110 107 217
        Male
    		 119 118 237

    End points

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    End points reporting groups
    Reporting group title
    LCZ696 (sacubitril/valsartan)
    Reporting group description
    		 Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.

    Reporting group title
    Olmesartan
    Reporting group description
    		 Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.

    Primary: Change from baseline in mean central aortic systolic pressure (CASP) at 12 weeks

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    End point title
    		 Change from baseline in mean central aortic systolic pressure (CASP) at 12 weeks
    End point description
    Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software. At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.
    End point type
    Primary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    207
    206
    Units: mmHg
        least squares mean (standard error)
    -12.57 ( 1.01 )
    -8.9 ( 1.01 )
    Statistical analysis title
    		 Change from baseline treatment difference in group
    Comparison groups
    LCZ696 (sacubitril/valsartan) v Olmesartan
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.45
         upper limit
    		 -0.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.42

    Secondary: Change from baseline in mean central pulse (CPP) pressure

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    End point title
    		 Change from baseline in mean central pulse (CPP) pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, and 52 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    229
    225
    Units: mmHg
    least squares mean (standard error)
        Baseline to Week 12 (n = 207, 206)
    -6.41 ( 0.69 )
    -3.96 ( 0.69 )
        Baseline to Week 52 (n = 209, 208)
    -7.16 ( 0.69 )
    -6.65 ( 0.69 )
    No statistical analyses for this end point

    Secondary: Change from baseline in mean pulse wave velocity (PWV)

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    End point title
    		 Change from baseline in mean pulse wave velocity (PWV)
    End point description
    Pulse wave velocity recordings were performed on patient while in a supine, face-up position. Tonometry was performed on the carotid simultaneously with the cuff inflation over the femoral artery. Two pulse wave velocity measures, meeting all quality control criteria were captured at baseline, week 12 and week 52.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks, and 52 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    229
    225
    Units: meter/second
    least squares mean (standard error)
        Baseline to week 12 (n= 192, 196)
    -0.68 ( 0.12 )
    -0.57 ( 0.12 )
        Baseline to week 52 ( n= 199, 199)
    -0.83 ( 0.13 )
    0.77 ( 0.13 )
    No statistical analyses for this end point

    Secondary: Change from baseline in mean central aortic systolic pressure (CASP) at 52 weeks

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    End point title
    		 Change from baseline in mean central aortic systolic pressure (CASP) at 52 weeks
    End point description
    Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software. At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.
    End point type
    Secondary
    End point timeframe
    baseline, 52 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    209
    208
    Units: mmHg
        least squares mean (standard error)
    -16.18 ( 0.96 )
    -14.7 ( 0.96 )
    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
    At the first study visit, the patient had his/her blood pressure (BP) measured in both arms; the arm in which the highest sitting SBP was found was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for 5 minutes, SBP were measured 3 times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1- to 2-minute intervals and the mean of those 3 measurements was used as the average sitting office BP for that visit.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks, and 52 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    229
    225
    Units: mmHg
    least squares mean (standard error)
        Baseline to week 12 (n=226, 222)
    -20.84 ( 1.06 )
    -14.57 ( 1.07 )
        Baseline to week 52 (n=226,223)
    -23.91 ( 0.98 )
    -21.45 ( 0.99 )
    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
    At the first study visit, the patient had his/her blood pressure (BP) measured in both arms; the arm in which the highest sitting SBP was found was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for 5 minutes, DBP were measured 3 times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1- to 2-minute intervals and the mean of those 3 measurements was used as the average sitting office BP for that visit.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks, and 52 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    229
    225
    Units: mmHg
    least squares mean (standard error)
        Baseline to week 12 (n=226, 222)
    -7.86 ( 0.58 )
    -5.58 ( 0.59 )
        Baseline to week 52 (n=226,223)
    -8.92 ( 0.57 )
    -7.85 ( 0.57 )
    No statistical analyses for this end point

    Secondary: Change from baseline in mean sitting pulse pressure (msPP)

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    End point title
    		 Change from baseline in mean sitting pulse pressure (msPP)
    End point description
    Mean sitting pulse pressure for each patient and visit was calculated as the difference between the calculated values of mean sitting systolic blood pressure and mean sitting diastolic blood pressure.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks, and 52 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    229
    225
    Units: mmHg
    least squares mean (standard error)
        Baseline to week 12 (n=226,222)
    -13.13 ( 0.82 )
    -8.86 ( 0.82 )
        Baseline to week 52 (n= 226, 223)
    -15.02 ( 0.79 )
    -13.58 ( 0.8 )
    No statistical analyses for this end point

    Secondary: Change from baseline in mean arterial pressure (MAP)

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    End point title
    		 Change from baseline in mean arterial pressure (MAP)
    End point description
    Mean arterial pressure (MAP) was calculated from mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) as (2 * msDBP + msSBP)/3.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks, and 52 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    229
    225
    Units: mmHg
    least squares mean (standard error)
        Baseline to week 12 (n=226, 222)
    -12.19 ( 0.68 )
    -8.57 ( 0.68 )
        Baseline to week 52 (n=226, 223)
    -13.92 ( 0.63 )
    -12.38 ( 0.64 )
    No statistical analyses for this end point

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

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    End point title
    		 Change from baseline in mean 24-hour systolic blood pressure (maSBP)
    End point description
    An Ambulatory Blood Pressure Monitor (ABPM) measured a participant's blood pressure over a 24 hour period using an automated validated monitoring device at baseline, week 12 and at week 52 starting one day before each visit. The 24 hour maSBP was calculated by taking the mean of all ambulatory systolic blood pressure readings for the 24 hour period.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, and 52 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    229
    225
    Units: mmHg
    least squares mean (standard error)
        Baseline to week 12 (n= 164, 162)
    -13.25 ( 0.62 )
    -9.14 ( 0.62 )
        Baseline to week 52 (n= 174, 176)
    -14.15 ( 0.59 )
    -14.32 ( 0.58 )
    No statistical analyses for this end point

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

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    End point title
    		 Change from baseline in mean 24-hour diastolic blood pressure (maDBP)
    End point description
    An Ambulatory Blood Pressure Monitor (ABPM) measured a participant's blood pressure over a 24 hour period using an automated validated monitoring device at baseline, week 12 and at week 52 starting one day before each visit. The 24 hour maDBP was calculated by taking the mean of all ambulatory systolic blood pressure readings for the 24 hour period.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, and 52 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    229
    225
    Units: mmHg
    least squares mean (standard error)
        Baseline to week 12 (n= 164, 162)
    -7.44 ( 0.37 )
    -5.48 ( 0.36 )
        Baseline to week 52 (n= 174, 176)
    -8.85 ( 0.35 )
    -8.44 ( 0.34 )
    No statistical analyses for this end point

    Secondary: Change from baseline in mean 24-hour ambulatory pulse pressure (maPP)

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    End point title
    		 Change from baseline in mean 24-hour ambulatory pulse pressure (maPP)
    End point description
    Mean 24 hour ambulatory pulse pressure was calculated as the difference between the mean 24 hour systolic and diastolic ambulatory blood pressure in corresponding visits i.e. baseline, week 12 and week 52.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, and 52 weeks
    End point values
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Number of subjects analysed
    229
    225
    Units: mmHg
    least squares mean (standard error)
        Baseline to Week 12 (n=164, 162 )
    -5.77 ( 0.35 )
    -3.69 ( 0.35 )
        Baseline to week 52 (n=174, 176)
    -5.26 ( 0.36 )
    -5.91 ( 0.35 )
    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.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    LCZ696 (sacubitril/valsartan)
    Reporting group description
    		 Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.

    Reporting group title
    Olmesartan
    Reporting group description
    		 Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.

    Serious adverse events
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 229 (6.99%)
    13 / 225 (5.78%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORTHOSTATIC HYPOTENSION
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ATELECTASIS
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PULMONARY PNEUMATOCELE
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    BLOOD PRESSURE INCREASED
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    HIP FRACTURE
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY CONTUSION
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    0 / 229 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TENDON RUPTURE
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR GRAFT OCCLUSION
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    2 / 229 (0.87%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    BRAIN STEM INFARCTION
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COAGULOPATHY
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IRON DEFICIENCY ANAEMIA
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    CATARACT
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    INGUINAL HERNIA
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS CHRONIC
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    OSTEOCHONDROSIS
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    APPENDICITIS
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DOUGLAS' ABSCESS
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 225 (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: 2%
    Non-serious adverse events
    		 LCZ696 (sacubitril/valsartan) Olmesartan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 229 (31.88%)
    55 / 225 (24.44%)
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    2 / 229 (0.87%)
    5 / 225 (2.22%)
         occurrences all number
    2
    6
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    12 / 229 (5.24%)
    12 / 225 (5.33%)
         occurrences all number
    15
    15
    HEADACHE
         subjects affected / exposed
    14 / 229 (6.11%)
    10 / 225 (4.44%)
         occurrences all number
    15
    13
    General disorders and administration site conditions
    OEDEMA PERIPHERAL
         subjects affected / exposed
    6 / 229 (2.62%)
    2 / 225 (0.89%)
         occurrences all number
    6
    2
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    6 / 229 (2.62%)
    5 / 225 (2.22%)
         occurrences all number
    7
    8
    ABDOMINAL PAIN
         subjects affected / exposed
    5 / 229 (2.18%)
    1 / 225 (0.44%)
         occurrences all number
    7
    1
    NAUSEA
         subjects affected / exposed
    5 / 229 (2.18%)
    2 / 225 (0.89%)
         occurrences all number
    6
    2
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    10 / 229 (4.37%)
    2 / 225 (0.89%)
         occurrences all number
    13
    2
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    5 / 229 (2.18%)
    7 / 225 (3.11%)
         occurrences all number
    7
    8
    BACK PAIN
         subjects affected / exposed
    3 / 229 (1.31%)
    10 / 225 (4.44%)
         occurrences all number
    3
    11
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    16 / 229 (6.99%)
    12 / 225 (5.33%)
         occurrences all number
    24
    16
    INFLUENZA
         subjects affected / exposed
    7 / 229 (3.06%)
    5 / 225 (2.22%)
         occurrences all number
    8
    5
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    6 / 229 (2.62%)
    6 / 225 (2.67%)
         occurrences all number
    7
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2014
    The primary purpose of protocol amendment to remove all references to an interim 12 week database lock. The 12 week primary analysis of the study was conducted at the end of the full 52 week study period. Corrections and inconsistencies in the protocol were also implemented with this amendment.

    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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