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    Clinical Trial Results:
    A multi-center, randomized, placebo-controlled patient and investigator-blinded study to explore the efficacy of oral sacubitril/valsartan in adult patients with non-obstructive hypertrophic cardiomyopathy (nHCM)

    Summary
    EudraCT number
    2019-003098-24
    Trial protocol
    DE   ES   GB   FI   GR  
    Global end of trial date
    22 Aug 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Aug 2024
    First version publication date
    23 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCZ696I12201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04164732
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 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
    22 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of LCZ696 on cardiopulmonary exercise test (CPET) parameters in patients with nHCM.
    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
    08 Jan 2020
    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: 7
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    46
    EEA total number of subjects
    32
    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)
    32
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Germany (4 sites), Greece (2 sites), Korea (2 sites), Spain (4 sites), United Kingdom (1 site), United States (5 sites)

    Pre-assignment
    Screening details
    Patients who met eligibility criteria entered a single-blind treatment run-in period. Patients who were unable to tolerate either placebo or the 50 mg p.o. b.i.d. dose level,were considered treatment run-in failures and were not randomized into the double-blind, placebo-controlled study

    Period 1
    Period 1 title
    Treatment run-in period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Run-in (All Participants)
    Arm description
    All patients received oral (p.o.) placebo b.i.d. for 2 weeks, followed by 50 mg p.o. b.i.d. of active LCZ696 for 2 weeks
    Arm type
    experimental and placebo

    Investigational medicinal product name
    placebo and LCZ696
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    all patients received oral (p.o.) placebo b.i.d. for 2 weeks followed by 50 mg p.o. of active LCZ696 b.i.d. for 2 weeks.

    Number of subjects in period 1
    Run-in (All Participants)
    Started
    46
    Completed
    40
    Not completed
    6
         Physician decision
    1
         Screen Failure
    1
         Adverse event, non-fatal
    4
    Period 2
    Period 2 title
    Randomized treatment period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    LCZ696 BID
    Arm description
    Patients were treated with LCZ696. The target dose level was 200 mg p.o. b.i.d.
    Arm type
    Experimental

    Investigational medicinal product name
    LCZ696
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants started at a LCZ696 100 mgp.o. b.i.d dose. After approximately 14days, patients who tolerated the 100 mgp.o. b.i.d. dose were up-titrated to 200mg p.o. b.i.d. dose, whereas those whodid not meet the safety criteria weretitrated back down to the 50 mg b.i.d.dose

    Arm title
    Placebo BID
    Arm description
    Placebo to LCZ696
    Arm type
    Placebo

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

    Number of subjects in period 2
    LCZ696 BID Placebo BID
    Started
    20
    20
    Randomized analysis set
    20
    20
    Per protocol analysis set
    19
    19
    Completed
    17
    19
    Not completed
    3
    1
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    -
         Protocol Deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment run-in period
    Reporting group description
    -

    Reporting group values
    Treatment run-in period Total
    Number of subjects
    46 46
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    32 32
        From 65-84 years
    14 14
        85 years and over
    0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    55.7 ( 13.42 ) -
    Sex: Female, Male
    Units: Participants
        Female
    12 12
        Male
    34 34
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    6 6
        White
    40 40

    End points

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    End points reporting groups
    Reporting group title
    Run-in (All Participants)
    Reporting group description
    All patients received oral (p.o.) placebo b.i.d. for 2 weeks, followed by 50 mg p.o. b.i.d. of active LCZ696 for 2 weeks
    Reporting group title
    LCZ696 BID
    Reporting group description
    Patients were treated with LCZ696. The target dose level was 200 mg p.o. b.i.d.

    Reporting group title
    Placebo BID
    Reporting group description
    Placebo to LCZ696

    Primary: Change from baseline in peak VO2 as measured by cardiopulmonary exercise test (CPET)

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    End point title
    Change from baseline in peak VO2 as measured by cardiopulmonary exercise test (CPET)
    End point description
    The primary analysis assessed the effect of LCZ696 on the change from baseline in peak Volume of Oxygen (VO2) (ml/kg/min) at week 50 compared to placebo, where baseline peak VO2 came from the screening/baseline CPET. An increase in peak VO2 (mL/kg/min)/positive change is considered beneficial for the patient.
    End point type
    Primary
    End point timeframe
    Baseline to 50 weeks
    End point values
    LCZ696 BID Placebo BID
    Number of subjects analysed
    18
    19
    Units: mL/kg/min
        least squares mean (confidence interval 90%)
    1.00 (-0.22 to 2.23)
    0.39 (-0.80 to 1.58)
    Statistical analysis title
    model-based arithmetic mean estimates
    Comparison groups
    LCZ696 BID v Placebo BID
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.5506
    Method
    longitudinal mixed effects (MMRM) model
    Parameter type
    Median difference (net)
    Point estimate
    0.61
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.71
         upper limit
    1.94

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 54 weeks.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Run-In Period Placebo
    Reporting group description
    Run-In Period Placebo

    Reporting group title
    Double-blind period placebo
    Reporting group description
    Double-blind period placebo

    Reporting group title
    Total
    Reporting group description
    Total

    Reporting group title
    Double-blind period LCZ696 100 mg
    Reporting group description
    Double-blind period LCZ696 100 mg

    Reporting group title
    Double-blind period LCZ696 200 mg
    Reporting group description
    Double-blind period LCZ696 200 mg

    Reporting group title
    Double-blind period LCZ696
    Reporting group description
    Double-blind period LCZ696

    Reporting group title
    Run-In LCZ696 50 mg
    Reporting group description
    Run-In LCZ696 50 mg

    Reporting group title
    Double-blind period LCZ696 50 mg
    Reporting group description
    Double-blind period LCZ696 50 mg

    Serious adverse events
    Run-In Period Placebo Double-blind period placebo Total Double-blind period LCZ696 100 mg Double-blind period LCZ696 200 mg Double-blind period LCZ696 Run-In LCZ696 50 mg Double-blind period LCZ696 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    3 / 46 (6.52%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
    3 / 20 (15.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Bundle branch block left
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4.99%
    Non-serious adverse events
    Run-In Period Placebo Double-blind period placebo Total Double-blind period LCZ696 100 mg Double-blind period LCZ696 200 mg Double-blind period LCZ696 Run-In LCZ696 50 mg Double-blind period LCZ696 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 46 (8.70%)
    10 / 20 (50.00%)
    26 / 46 (56.52%)
    6 / 20 (30.00%)
    7 / 17 (41.18%)
    12 / 20 (60.00%)
    4 / 43 (9.30%)
    1 / 1 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    4 / 46 (8.70%)
    0 / 20 (0.00%)
    2 / 17 (11.76%)
    3 / 20 (15.00%)
    1 / 43 (2.33%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    4
    0
    2
    3
    1
    1
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 20 (5.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 20 (5.00%)
    2 / 46 (4.35%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    0
    1
    1
    0
    0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Injury, poisoning and procedural complications
    Foreign body in eye
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 20 (5.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 20 (5.00%)
    5 / 46 (10.87%)
    0 / 20 (0.00%)
    2 / 17 (11.76%)
    2 / 20 (10.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    5
    0
    2
    2
    0
    0
    Syncope
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    2
    2
    0
    0
    Tension headache
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    1
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    2 / 46 (4.35%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    2
    0
    1
    1
    0
    0
    Gastrointestinal sounds abnormal
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    0
    Gastric disorder
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    3 / 46 (6.52%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    3
    0
    1
    1
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 20 (10.00%)
    2 / 46 (4.35%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    2 / 46 (4.35%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    2
    0
    1
    1
    0
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 20 (5.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 20 (5.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 46 (0.00%)
    5 / 20 (25.00%)
    5 / 46 (10.87%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    5
    5
    0
    0
    0
    0
    0
    Diverticulitis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    1
    1
    0
    Metabolism and nutrition disorders
    Abnormal loss of weight
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 20 (0.00%)
    1 / 46 (2.17%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    0
    Gout
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 20 (5.00%)
    1 / 46 (2.17%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2020
    • Protocol summary - Key inclusion and exclusion criteria were corrected to reflect the criteria listed in Section 5 of the protocol. • Section 3 Study design - Clarified the use of safety criteria to assess tolerability of study medication. • Section 4.2 Rationale for selection of patient population - Added rationale for the NT-proBNP cutoff required to screen asymptomatic patients. • Section 4.7 Risks and benefits - Clarified risk of fetal harm by study medication if women of childbearing potential become pregnant while on study medication. • Section 5.1 Inclusion criteria - Inclusion criteria 4 has been updated to allow asymptomatic/NYHA Class I patients with peak VO2 of 80% to enroll in the study to harmonize with exclusion criteria 4. • Section 5.2 Exclusion criteria - Exclusion criteria 3 was clarified to exclude only those patients with a history of atrial fibrillation within 6 months of the screening/baseline visit. • Section 8 Visit schedule and assessments - Corrected a typographical error to make clear the requirement for recording adverse events during the screening/baseline period. • Section 8.4.4 Laboratory evaluations - Added clarification that plasma samples instead of serum samples can be collected for local laboratory analysis as per local practice. • Section 10.2.1 Liver safety monitoring - Correction made to indicate that results of local liver chemistry tests associated with a liver event should be recorded in source documents rather than in the CRF. • Section 12.7 Interim Analysis - Added clarification that the planned interim analysis will also include review of safety data.
    01 Apr 2022
    • Section 2 Objectives and Endpoints - Added information in Table 2.1 (Objectives and related endpoints) about collection of NYHA as an exploratory endpoint. • Section 5.1 Inclusion criteria - Added additional text to emphasize to sites that Informed Consent must be signed prior to discontinuation of ACE-I/ARB during the >36 hour washout period, if applicable. • Section 8 Visit schedule and assessments - Added the specific time points in Table 8.1 for data collection of NYHA class information at screening/baseline and Week 50 or EOS (if the patient discontinues the study prior to the Week 50 assessment). - Added Table 8.2 NYHA functional class table with standard descriptions of each functional class • Section 10.1.3 SAE reporting - Added additional text for clarification on investigator reporting timelines for SAEs

    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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