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    Clinical Trial Results:
    A randomized, double-blind, active-controlled study to assess the effect of LCZ696 compared with enalapril to improve exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF)

    Summary
    EudraCT number
    		 2015-004632-35
    Trial protocol
    		 DE  
    Global end of trial date
    25 Nov 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 May 2021
    First version publication date
    02 Oct 2020
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Additional text added in the field Adverse Events reporting additional description.

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCZ696BDE01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02768298
    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, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, 41 613241111, Novartis.email@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
    25 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate the superiority of LCZ696 200 mg bid compared to enalapril 10 mg bid in improving exercise tolerance (peak respiratory oxygen uptake (VO2peak), adjusted to body weight) as assessed by cardio-pulmonary-exercise testing (CPET) in patients with stable chronic heart failure (NYHA III) and reduced ejection fraction (LVEF ≤ 40%) after 3 months 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. Regarding rescue medication, patients received open-label angiotensin converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) during the study ONLY if the study medication was discontinued either temporarily or permanently. A 36 hours washout phase of study drug was needed before start of an ACEI.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jul 2016
    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
    Germany: 201
    Worldwide total number of subjects
    201
    EEA total number of subjects
    201
    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)
    77
    From 65 to 84 years
    118
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 34 investigative sites in Germany.

    Pre-assignment
    Screening details
    		 Participants were randomized 1:1 to receive either LCZ696 or enalapril during the double-blind period.

    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
    Arm description
    		 LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 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 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks

    Arm title
    		 Enalapril
    Arm description
    		 Enalapril 5 mg oral twice daily (bid) for 2 weeks followed by enalapril 10 mg oral bid for 10 weeks. Patients who prior Screening were at a stable daily dose of enalapril above 10 mg per day (or corresponding doses of other ACEI/ARB) started the study at a dose of enalapril 10 mg bid.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Enalapril 5 mg oral twice daily (bid) for 2 weeks followed by enalapril 10 mg oral bid for 10 weeks. Patients who prior Screening were at a stable daily dose of enalapril above 10 mg per day (or corresponding doses of other ACEI/ARB) started the study at a dose of enalapril 10 mg bid.

    Number of subjects in period 1
    		LCZ696 Enalapril
    Started
    103
    98
    Completed
    99
    91
    Not completed
    4
    7
         Adverse event, serious fatal
    2
    1
         Adverse event, non-fatal
    1
    4
         Non-compliance with study treatment
    -
    1
         Withdrawal of informed consent
    -
    1
         Subject/guardian decision
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.

    Reporting group title
    Enalapril
    Reporting group description
    		 Enalapril 5 mg oral twice daily (bid) for 2 weeks followed by enalapril 10 mg oral bid for 10 weeks. Patients who prior Screening were at a stable daily dose of enalapril above 10 mg per day (or corresponding doses of other ACEI/ARB) started the study at a dose of enalapril 10 mg bid.

    Reporting group values
    		 LCZ696 Enalapril Total
    Number of subjects
    		 103 98 201
    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)
    		 43 34 77
        From 65-84 years
    		 57 61 118
        85 years and over
    		 3 3 6
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 66.1 ( 10.792 ) 67.6 ( 9.961 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 17 21 38
        Male
    		 86 77 163
    Race/Ethnicity, Customized
    Units: Subjects
        Caucassian
    		 101 96 197
        Black
    		 0 1 1
        Other
    		 2 1 3

    End points

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    End points reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.

    Reporting group title
    Enalapril
    Reporting group description
    		 Enalapril 5 mg oral twice daily (bid) for 2 weeks followed by enalapril 10 mg oral bid for 10 weeks. Patients who prior Screening were at a stable daily dose of enalapril above 10 mg per day (or corresponding doses of other ACEI/ARB) started the study at a dose of enalapril 10 mg bid.

    Primary: Change from baseline in peak respiratory oxygen uptake (VO2peak) adjusted to body weight) after 3 months of treatment

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    End point title
    		 Change from baseline in peak respiratory oxygen uptake (VO2peak) adjusted to body weight) after 3 months of treatment
    End point description
    Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. One of the parameters attained by this test is the peak respiratory oxygen uptake (VO2peak). CPET to assess VO2peak was performed at a cycle ergometer at baseline (Visit 2, 9 days prior randomization) and after 6 weeks and 3 months of treatment (Visit 6 and Visit 7, respectively). The VO2peak adjusted to body weight was calculated based on the corresponding visit’s VO2peak (unadjusted) and body weight data by using the following formula: VO2peak (unadjusted)/body weight. Higher values of VO2peak indicate less symptom severity and therefore a positive change from baseline indicates improvement.
    End point type
    Primary
    End point timeframe
    Baseline, 3 months
    End point values
    		 LCZ696 Enalapril
    Number of subjects analysed
    98
    90
    Units: mL/kg/min
        least squares mean (standard error)
    0.51 ( 0.180 )
    0.19 ( 0.188 )
    Statistical analysis title
    		 VO2peak- 3 months
    Comparison groups
    LCZ696 v Enalapril
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2327
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares (LS) Mean
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.268

    Secondary: Change from baseline in peak respiratory oxygen uptake (VO2peak) adjusted to body weight) after 6 weeks of treatment

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    End point title
    		 Change from baseline in peak respiratory oxygen uptake (VO2peak) adjusted to body weight) after 6 weeks of treatment
    End point description
    Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. One of the parameters attained by this test is the peak respiratory oxygen uptake (VO2peak). CPET to assess VO2peak was performed at a cycle ergometer at baseline (Visit 2, 9 days prior randomization) and after 6 weeks and 3 months of treatment (Visit 6 and Visit 7, respectively). The VO2peak adjusted to body weight was calculated based on the corresponding visit’s VO2peak (unadjusted) and body weight data by using the following formula: VO2peak (unadjusted)/body weight. A positive change from baseline indicates less symptom severity.
    End point type
    Secondary
    End point timeframe
    Baseline, 6 weeks
    End point values
    		 LCZ696 Enalapril
    Number of subjects analysed
    97
    88
    Units: mL/kg/min
        least squares mean (standard error)
    0.28 ( 0.185 )
    0.42 ( 0.195 )
    Statistical analysis title
    		 VO2peak
    Comparison groups
    LCZ696 v Enalapril
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6247
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.68
         upper limit
    		 0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.277

    Secondary: Change from baseline in the minute ventilation (VE) to carbon dioxide output slope (VE/VCO2 slope)

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    End point title
    		 Change from baseline in the minute ventilation (VE) to carbon dioxide output slope (VE/VCO2 slope)
    End point description
    Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. One of the parameters attained by this test is the minute ventilation (VE) to carbon dioxide output slope (VE/VCO2 slope). High values of VE/VCO2 slope resembles the inability to eliminate CO2 by respiration (inefficient ventilation). A negative change from baseline indicates less symptom severity.
    End point type
    Secondary
    End point timeframe
    Baseline, 6 weeks, 3 months
    End point values
    		 LCZ696 Enalapril
    Number of subjects analysed
    103
    98
    Units: no units
    least squares mean (standard error)
        6 weeks
    -1.05 ( 0.597 )
    0.18 ( 0.629 )
        3 months
    0.76 ( 0.542 )
    -0.07 ( 0.575 )
    Statistical analysis title
    		 VE/VCO2 slope
    Statistical analysis description
    6 weeks
    Comparison groups
    LCZ696 v Enalapril
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1678
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.98
         upper limit
    		 0.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.888
    Statistical analysis title
    		 VE/VCO2 slope
    Statistical analysis description
    3 months
    Comparison groups
    LCZ696 v Enalapril
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3052
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.77
         upper limit
    		 2.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.809

    Secondary: Change from baseline in exercise capacity (watt) at ventilatory anaerobic threshold (VAT)

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    End point title
    		 Change from baseline in exercise capacity (watt) at ventilatory anaerobic threshold (VAT)
    End point description
    Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. CPET was performed at a cycle ergometer with a workload that started at 10 watts (W) and then increased by 10W for each 1-minute stage. Exercise capacity assessed as workload in watts was determined at the ventilatory anaerobic threshold (VAT) which represents the transition from aerobic to partially anaerobic glucose metabolism in muscle, leading to increasing carbon dioxide exhalation in comparison to oxygen uptake. A positive change from baseline in exercise capacity (watt) indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 6 weeks, 3 months
    End point values
    		 LCZ696 Enalapril
    Number of subjects analysed
    103
    98
    Units: Watt
    least squares mean (standard error)
        6 weeks
    1.71 ( 1.168 )
    0.83 ( 1.234 )
        3 months
    2.45 ( 1.436 )
    -0.83 ( 1.483 )
    Statistical analysis title
    		 Ventilatory anaerobic threshold
    Statistical analysis description
    6 weeks
    Comparison groups
    LCZ696 v Enalapril
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6181
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.58
         upper limit
    		 4.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.744
    Statistical analysis title
    		 Ventilatory anaerobic threshold
    Statistical analysis description
    3 months
    Comparison groups
    LCZ696 v Enalapril
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1254
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    3.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 7.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.124

    Secondary: Change from baseline in rate of perceived exertion (perceived dyspnea and perceived fatigue) during exercise assessed by Borg scale

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    End point title
    		 Change from baseline in rate of perceived exertion (perceived dyspnea and perceived fatigue) during exercise assessed by Borg scale
    End point description
    The individually perceived exertion, in terms of perceived dyspnea and perceived fatigue, during cardiopulmonary exercise testing (CPET) was assessed by Borg scale which is a 15 point scale, starting from 6 which indicates "No exertion at all" to 20 which means "Maximal exertion". Change in Borg scale for both perceived dyspnea and perceived fatigue were measured at different time points at Baseline (Visit 2, 9 days prior randomization) and 3 months of treatment (Visit 7). Maximum value among the time points at every visit was used for the analysis. A negative change from baseline in Borg value of perceived dyspnea and perceived fatigue indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 3 months
    End point values
    		 LCZ696 Enalapril
    Number of subjects analysed
    103
    98
    Units: Score on scale
    least squares mean (standard error)
        Borg value perceived dyspnea
    -0.19 ( 0.212 )
    0.11 ( 0.223 )
        Borg value perceived fatigue
    -0.04 ( 0.167 )
    -0.20 ( 0.178 )
    Statistical analysis title
    		 Borg value dyspnea
    Comparison groups
    LCZ696 v Enalapril
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3432
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.317
    Statistical analysis title
    		 Borg value fatigue
    Comparison groups
    LCZ696 v Enalapril
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5319
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 0.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.251

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days (16 weeks on average).
    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
    22.1
    Reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696

    Reporting group title
    Enalapril
    Reporting group description
    		 Enalapril

    Serious adverse events
    		 LCZ696 Enalapril
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 103 (11.65%)
    14 / 98 (14.29%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    1
    Investigations
    Angiocardiogram
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio abnormal
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Glioblastoma
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 103 (1.94%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 103 (0.97%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 103 (1.94%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 103 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular stent occlusion
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 103 (0.97%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 103 (1.94%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LCZ696 Enalapril
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 103 (50.49%)
    36 / 98 (36.73%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    27 / 103 (26.21%)
    11 / 98 (11.22%)
         occurrences all number
    29
    11
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 103 (13.59%)
    6 / 98 (6.12%)
         occurrences all number
    14
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 103 (1.94%)
    7 / 98 (7.14%)
         occurrences all number
    2
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 103 (2.91%)
    9 / 98 (9.18%)
         occurrences all number
    3
    9
    Dyspnoea
         subjects affected / exposed
    2 / 103 (1.94%)
    6 / 98 (6.12%)
         occurrences all number
    2
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 103 (8.74%)
    3 / 98 (3.06%)
         occurrences all number
    10
    3
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    9 / 103 (8.74%)
    3 / 98 (3.06%)
         occurrences all number
    10
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Apr 2016
    The section “Other concomitant treatment – ACEIs and ARBs – was reworded to clearly state that both ACEI and ARB were prohibited during treatment with double-blind study medication. If ACEI and/or ARB were initiated, study medication had to be discontinued. It was clarified that 36 hour wash-out period was necessary for ACEI, but not for ARB.
    05 Dec 2017
    Eligibility was adapted to clarify two exclusion criteria: planned heart transplant or ventricular assistance device (VAD) during the expected study duration of 14 weeks, and diagnosed long QT syndrome. It was explicitly stated in section “Other concomitant medication” that concomitant heart failure medication should be stable 4 weeks prior to screening Visit 1 and until randomization Visit 3.
    21 Jan 2019
    The primary packaging of enalapril 5 mg and 10 mg tablets was updated.
    24 Jul 2019
    The term “lean body weight” was changed to “body weight” throughout the protocol and therefore the primary (adjusted VO2peak after 3 months of treatment) and secondary endpoint (adjusted VO2peak after 6 weeks of treatment) were changed. RER=1 was exchanged to ventilatory anaerobic threshold (VAT) for the secondary endpoint “Exercise capacity (Watt)”.

    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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    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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