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    Clinical Trial Results:
    Effect of ivabradine versus placebo on cardiac function, exercise capacity, and neuroendocrine activation in patients with Chronic Heart Failure with Preserved left ventricular Ejection Fraction An 8-month, randomised double-blind, placebo controlled, international, multicentre study.

    Summary
    EudraCT number
    		 2012-002742-20
    Trial protocol
    		 HU   PT   IT   DE   BE   GB   NL   ES   CZ   AT   SI  
    Global end of trial date
    29 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Mar 2017
    First version publication date
    04 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-16257-101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50, rue Carnot, Suresnes, France, 92284
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
    Sponsor organisation name
    Laboratorios Servier SL
    Sponsor organisation address
    Avd de los Madronos 33, Madrid, Spain, 28043
    Public contact
    M. De Quintana Barajas, Laboratorios Servier SL, +34 91 748 96 30,
    Scientific contact
    M. De Quintana Barajas, Laboratorios Servier SL, +34 91 748 96 30,
    Sponsor organisation name
    Servier Research and Development Ltd
    Sponsor organisation address
    Rowley, Wexham Springs, Framewood Road, Wexham, United Kingdom, Slough SL3 6PJ
    Public contact
    J. Crepineau, Servier Research and Development Ltd, +44 1 753 6627 44,
    Scientific contact
    J. Crepineau, Servier Research and Development Ltd, +44 1 753 6627 44,
    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
    29 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Feb 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the effect of ivabradine compared to placebo on the cardiac function, the exercise capacity and the neuroendocrine activation in patients with chronic heart failure over an 8-month treatment period.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jun 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 7
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Russian Federation: 32
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    United Kingdom: 14
    Worldwide total number of subjects
    179
    EEA total number of subjects
    116
    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)
    34
    From 65 to 84 years
    136
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 The number of patients included was substantially less (45%) than the 400 proposed in the protocol because of the difficulties in meeting the strict selection criteria designed to ensure to select an appropriate HFPEF population.

    Pre-assignment
    Screening details
    		 Patients were men or women aged at least 50 years with Chronic HF and preserved Ejection Fraction (HF-PEF) and HR ≥ 70 bpm.

    Period 1
    Period 1 title
    double-blind treatment period (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
    		 Ivabradine
    Arm description
    		 Ivabradine 2.5 mg, 5 mg or 7.5 mg: oral administration twice daily (b.i.d.) of one tablet during meals.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ivabradine
    Investigational medicinal product code
    S 16257
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivabradine tablets were administered twice daily (morning and evening) during meals with a starting dose of 5 mg twice daily. The dose of ivabradine could be titrated depending on the patient’s ECG resting HR and tolerability to a lower dose (2.5 mg) or a higher dose (7.5 mg b.i.d. then 10 mg b.i.d. before Amendment No. 8). This could be done at any visit and multiple titrations were permitted.

    Arm title
    		 Matching placebo
    Arm description
    		 Matching placebo: oral administration twice daily (b.i.d.) of one tablet during meals.
    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
    Matching placebo tablets were administered twice daily (morning and evening) during meals with a starting dose of 5 mg twice daily. The dose of placebo could be titrated depending on the patient’s ECG resting HR and tolerability to a lower dose (2.5 mg) or a higher dose (7.5 mg b.i.d. then 10 mg b.i.d. before Amendment No. 8). This could be done at any visit and multiple titrations were permitted.

    Number of subjects in period 1
    		Ivabradine Matching placebo
    Started
    95
    84
    Completed
    76
    77
    Not completed
    19
    7
         Adverse event, serious fatal
    3
    -
         Non medical reason
    6
    2
         Adverse event, non-fatal
    8
    5
         Other reason
    1
    -
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ivabradine
    Reporting group description
    		 Ivabradine 2.5 mg, 5 mg or 7.5 mg: oral administration twice daily (b.i.d.) of one tablet during meals.

    Reporting group title
    Matching placebo
    Reporting group description
    		 Matching placebo: oral administration twice daily (b.i.d.) of one tablet during meals.

    Reporting group values
    		 Ivabradine Matching placebo Total
    Number of subjects
    		 95 84 179
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 18 16 34
        From 65-84 years
    		 70 66 136
        85 years and over
    		 7 2 9
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.4 ( 8.6 ) 71.8 ( 9.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 59 57 116
        Male
    		 36 27 63
    Subject analysis sets

    Subject analysis set title
    Randomized Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients to whom a therapeutic unit was randomly assigned

    Subject analysis sets values
    		 Randomized Set
    Number of subjects
    179
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    34
        From 65-84 years
    136
        85 years and over
    9
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71.6 ( 8.9 )
    Gender categorical
    Units: Subjects
        Female
    116
        Male
    63

    End points

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    End points reporting groups
    Reporting group title
    Ivabradine
    Reporting group description
    		 Ivabradine 2.5 mg, 5 mg or 7.5 mg: oral administration twice daily (b.i.d.) of one tablet during meals.

    Reporting group title
    Matching placebo
    Reporting group description
    		 Matching placebo: oral administration twice daily (b.i.d.) of one tablet during meals.

    Subject analysis set title
    Randomized Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients to whom a therapeutic unit was randomly assigned

    Primary: E/e’ – Change from baseline to last post-baseline

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    End point title
    		 E/e’ – Change from baseline to last post-baseline
    End point description
    Co-primary endpoint: (E= early diastolic mitral flow velocity, e'= mean of mitral annular lateral and septal proto diastolic velocities) an estimate of LV filling pressures based on Echo-Doppler measures.
    End point type
    Primary
    End point timeframe
    A comprehensive transthoracic echocardiography was performed at the ASSE, M2 and M8 visits. The E/e’ ratio was described in terms of value at baseline, last post-baseline value and change from baseline to last post-baseline value
    End point values
    		 Ivabradine Matching placebo
    Number of subjects analysed
    84
    83
    Units: no unit
        arithmetic mean (standard deviation)
    0.9 ( 3.8 )
    -0.9 ( 6.4 )
    Statistical analysis title
    		 Ivabradine versus placebo effect
    Comparison groups
    Ivabradine v Matching placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.135 [1]
    Method
    		 Ancova adj. on geogra. area and baseline
    Parameter type
    		 Arithmetic group means (final values)
    Point estimate
    1.37
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 2.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.68
    Notes
    [1] - Adjusted p-value for Hommel procedure (to be compared to 0.10).

    Primary: Total distance in 6MWT – Change from baseline to last post-baseline

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    End point title
    		 Total distance in 6MWT – Change from baseline to last post-baseline
    End point description
    Co-primary endpoint.
    End point type
    Primary
    End point timeframe
    The total distance walked in 6 minutes was performed at ASSE, D000, M002, M004 and M008. The 6MWT was described in terms of value at baseline, last post baseline value and change from baseline to last post-baseline value.
    End point values
    		 Ivabradine Matching placebo
    Number of subjects analysed
    84
    84
    Units: meter
        arithmetic mean (standard deviation)
    4.3 ( 50 )
    7.9 ( 67.9 )
    Statistical analysis title
    		 Ivabradine versus placebo effect
    Comparison groups
    Ivabradine v Matching placebo
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.882 [2]
    Method
    		 Ancova adj. on geogra. area and baseline
    Parameter type
    		 Arithmetic group means (final values)
    Point estimate
    -3.75
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -19.14
         upper limit
    		 11.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.3
    Notes
    [2] - Adjusted p-value for Hommel procedure (to be compared to 0.10).

    Primary: NT-proBNP – Change from baseline to last post-baseline

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    End point title
    		 NT-proBNP – Change from baseline to last post-baseline
    End point description
    Co-primary endpoint: Plasma concentration of N Terminal-pro Beta type Natriuretic Peptide centrally measured using blood samples.
    End point type
    Primary
    End point timeframe
    NT-proBNP samples collected at D000 (baseline value), M002, M004 and M008. Log-transformation of mean values at baseline and last post-baseline value; change calculated as ratio of baseline value to post-baseline value.
    End point values
    		 Ivabradine Matching placebo
    Number of subjects analysed
    83
    82
    Units: pg/mL
        geometric mean (inter-quartile range (Q1-Q3))
    1.1 (0.8 to 1.5)
    1.1 (0.8 to 1.4)
    Statistical analysis title
    		 Ivabradine versus placebo effect
    Comparison groups
    Ivabradine v Matching placebo
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.882 [3]
    Method
    		 Ancova adj. on geogra. area and baseline
    Parameter type
    		 Geometric group means (final values)
    Point estimate
    1.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.19
    Notes
    [3] - Adjusted p-value for Hommel procedure (to be compared to 0.10).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Emergent adverse events on treatment were defined as all adverse events that occurred or worsened (in terms of intensity) or became serious between the first IMP intake date and the last IMP intake date +2 days (both included)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Ivabradine
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Ivabradine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 84 (25.00%)
    33 / 94 (35.11%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic thrombosis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 84 (2.38%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (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
    Anaemia postoperative
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    5 / 84 (5.95%)
    5 / 94 (5.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         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
    5 / 84 (5.95%)
    6 / 94 (6.38%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (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
    Dizziness
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         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
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Barrett's oesophagus
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 84 (2.38%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lymph node tuberculosis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Ivabradine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 84 (60.71%)
    57 / 94 (60.64%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon adenoma
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 94 (2.13%)
         occurrences all number
    0
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 84 (8.33%)
    11 / 94 (11.70%)
         occurrences all number
    7
    11
    Hypotension
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 94 (2.13%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 94 (1.06%)
         occurrences all number
    2
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 84 (0.00%)
    4 / 94 (4.26%)
         occurrences all number
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 84 (1.19%)
    3 / 94 (3.19%)
         occurrences all number
    1
    4
    Investigations
    Blood pressure increased
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 94 (1.06%)
         occurrences all number
    2
    1
    Heart rate decreased
         subjects affected / exposed
    1 / 84 (1.19%)
    5 / 94 (5.32%)
         occurrences all number
    1
    5
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 84 (2.38%)
    2 / 94 (2.13%)
         occurrences all number
    2
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 84 (3.57%)
    2 / 94 (2.13%)
         occurrences all number
    4
    2
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 94 (2.13%)
         occurrences all number
    1
    2
    Bradycardia
         subjects affected / exposed
    2 / 84 (2.38%)
    3 / 94 (3.19%)
         occurrences all number
    2
    3
    Cardiac failure
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 94 (2.13%)
         occurrences all number
    5
    2
    Sinus tachycardia
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 94 (0.00%)
         occurrences all number
    2
    0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 94 (2.13%)
         occurrences all number
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 84 (7.14%)
    2 / 94 (2.13%)
         occurrences all number
    7
    2
    Headache
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 94 (0.00%)
         occurrences all number
    2
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 94 (2.13%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 84 (1.19%)
    4 / 94 (4.26%)
         occurrences all number
    1
    4
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 94 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Photopsia
         subjects affected / exposed
    0 / 84 (0.00%)
    3 / 94 (3.19%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 94 (2.13%)
         occurrences all number
    1
    2
    Diarrhoea
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 94 (1.06%)
         occurrences all number
    2
    1
    Dental caries
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 94 (2.13%)
         occurrences all number
    0
    2
    Dyspepsia
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 94 (2.13%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 94 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 94 (0.00%)
         occurrences all number
    2
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 94 (1.06%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 94 (2.13%)
         occurrences all number
    1
    2
    Muscle spasms
         subjects affected / exposed
    4 / 84 (4.76%)
    0 / 94 (0.00%)
         occurrences all number
    4
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 94 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 84 (0.00%)
    3 / 94 (3.19%)
         occurrences all number
    0
    3
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 84 (3.57%)
    0 / 94 (0.00%)
         occurrences all number
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 94 (1.06%)
         occurrences all number
    2
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 94 (2.13%)
         occurrences all number
    0
    2
    Hyperuricaemia
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 94 (2.13%)
         occurrences all number
    0
    2
    Hyperkalaemia
         subjects affected / exposed
    2 / 84 (2.38%)
    2 / 94 (2.13%)
         occurrences all number
    2
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2013
    Amendment No. 6, was applicable in all countries. The main changes were as following: - Measurement of pulse rate before the 6MWT, immediately at the end of the test, and at 1 and 10 minutes after the test. - Addition of the ventricular-arterial coupling defined by the ratio Ea/Ees as secondary efficacy criterion. - Fasting conditions for blood sampling were not required. - A dose margin of diuretics within 4 weeks prior to selection was accepted. - Addition of large mitral calcifications and of aortic or mitral valvular surgery as non-selection criteria. - Rehabilitation program was accepted only if it was started at least 3 months prior to selection, and provided that the patients were under maintenance phase of rehabilitation at selection. - Clarification on the biomarkers analysis. - Addition of Slovenia as participating country. - Planification of the cardiac MRI sub-study in UK. - Slight modification of the cut-off of the NT-proBNP and BNP levels as inclusion criteria (NT-proBNP > 300 pg/mL or BNP > 100 pg/mL replaced by ≥ 300 pg/mL or ≥ 100 pg/mL respectively). - Addition of a check at inclusion that the patient was still able to perform the 6MWT. - Atrio-ventricular block of 3rd degree was considered as a contra-indication of the IMP and was consequently a withdrawal criterion. - Clarification of the process of echocardiography’s review and of the instructions for echocardiography. - BioStorage Technologies were named responsible for the long-term storage of non genomic and genomic analyses.
    31 Mar 2014
    Amendment No. 7 was applicable in all countries. The main changes were as following: - Extension of the enrolment period. - Study completion update. - Possibility to perform the blood sampling at selection before any other investigations. - Decrease of the cut-off of the NT-proBNP and BNP levels (NT-proBNP ≥ 220 pg/mL or BNP ≥ 80 pg/mL) as inclusion criteria. - The NT-proBNP or BNP values could be checked at the selection visit if the results were available. - Decrease of the cut-off of the LVEF (≥ 45% and < 50%) as selection criterion. - Previous aortic surgery or intervention allowed if at least 1 year before selection. - Previous treatment with ivabradine allowed if stopped since at least 6 months before selection. - Possibility for patients to be re-enrolled in the study. - Decrease of the cut-off of creatinine clearance (> 15 and < 30 mL/min/1.73m²) at selection and inclusion. - Setting-up of a Data Monitoring Committee.
    19 Jun 2014
    Amendment No. 8, was applicable in all countries. The main changes were as following: - The highest 10 mg dose was removed from the study. - Korea and Taiwan were added as participating countries.
    14 Jan 2015
    Amendment No. 10, was applicable in all countries. The main changes were as following: - Intake of the grapefruit juice should be avoided. - Change of the method of calculation of the TEI index and removal of the IVCT criterion. - The 6MWT could be performed before the echocardiography in exceptional circumstances. - The samples for NT-proBNP and other biomarkers analyses were sent on a regular basis to the central laboratory CDL Pharma
    04 May 2015
    Amendment No. 12, was applicable in all countries. An interim analysis was added.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 Aug 2015
    The recruitment period was extended for 8 months by Amendment 7, but further prolongation was abandoned.
    -

    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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