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    The EU Clinical Trials Register currently displays   43936   clinical trials with a EudraCT protocol, of which   7310   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Clinical Trial Results:
    Determination of the efficacious and safe dose of ivabradine in paediatric patients with dilated cardiomyopathy and symptomatic chronic heart failure aged from 6 months to less than 18 years. A randomised, double-blind, multicentre, placebo controlled, phase II/III dose-finding study with a PK/PD characterisation and a 1 year efficacy/safety evaluation.

    Summary
    EudraCT number
    2011-001292-39
    Trial protocol
    FI   GB   BE   SE   DE   PT   IT   HU   BG   DK   ES  
    Global end of trial date
    26 Feb 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Feb 2016
    First version publication date
    31 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-16257-090
    Additional study identifiers
    ISRCTN number
    ISRCTN60567801
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier (I.R.I.S.)
    Sponsor organisation address
    50, rue Carnot, Suresnes Cedex, France, 92284
    Public contact
    TIP (Therapeutic Innovation Pole), Institut de Recherches Internationales Servier, +33 1.55.72.43.66, clinicaltrials@servier.com
    Scientific contact
    TIP (Therapeutic Innovation Pole), Institut de Recherches Internationales Servier, +33 1.55.72.43.66, clinicaltrials@servier.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000628-PIP01-09
    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
    26 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the optimal dose of ivabradine to reach the target heart rate reduction (HRR) of 20% without inducing a bradycardia (i.e. HR should be greater than a predefined HR threshold by age subset) and/or signs or symptoms related to bradycardia, ­To assess the pharmacokinetic (PK) parameters of ivabradine and its active metabolite S 18982 after repeated oral administrations, ­To assess the PKPD relationship of ivabradine and its active metabolite S 18982 using heart rate as evaluation criterion.
    Protection of trial subjects
    Treatment could be prematurely and definitively discontinued by the investigator for any of the following reasons: -Unwillingness of the investigator/patient/parents to continue with the study. Study drug not tolerated: a premature treatment discontinuation could be decided in case of any suspected adverse reaction which caused permanent discomfort to the patient and led to interruption of his/her usual activities, or in case of a suspected adverse reaction which was considered (by the investigator) as a safety issue. -Study drug no longer appropriate: the study drug would be considered as no longer appropriate in case of prolonged loss of sinus rhythm (e.g. permanent atrial fibrillation) or in case of pacemaker implantation. -Study drug considered as contraindicated
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Oct 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Romania: 6
    Worldwide total number of subjects
    116
    EEA total number of subjects
    84
    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)
    28
    Children (2-11 years)
    69
    Adolescents (12-17 years)
    19
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients to be included were male or female, aged from 6 months to less than 18 years old, with DCM, with a CHF Class II to IV (NYHA or Ross classification), left ventricular ejection fraction (LVEF) ≤45% documented by echocardiography, receiving their usual treatment for CHF at the optimal dose, in sinus rhythm.

    Pre-assignment
    Screening details
    With a planned maximum duration of 7 days. Eligible patients were randomised by IRS, with a stratification by age in order to obtain the balance of treatment groups within each age subset. These latter were based on age subsets defined for dose titration

    Pre-assignment period milestones
    Number of subjects started
    116
    Number of subjects completed
    116

    Period 1
    Period 1 title
    Whole study period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ivabradine
    Arm description
    Patients taking Ivabradine
    Arm type
    Experimental

    Investigational medicinal product name
    Ivabradine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment (double-blind ivabradine or placebo) was taken orally twice daily (either oral liquid paediatric formulation or matching placebo, or adult tablets or matching placebo tablet for patients ≥40 kg (and able to swallow tablets, older than 6 years), in the morning and in the evening during meals at 12-hour intervals. The galenic form to be taken (oral solution or tablets) was defined once at D0 and did not change throughout the study. A maximum of five doses of ivabradine or matching placebo was to be potentially tested in each patient: the doses were adapted every 2 weeks, through a maximum of 4 dose levels, according to the titration rules taking into account the age, the weight, the achievement or not of the HRR target (reduction of at least 20% of baseline HR) and the occurrence or not of bradycardia

    Arm title
    Placebo
    Arm description
    Patients taking placebo
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment (double-blind ivabradine or placebo) was taken orally twice daily (either oral solution paediatric formulation or matching placebo, or adult tablets or matching placebo tablet for patients ≥40 kg (and able to swallow tablets, older than 6 years), in the morning and in the evening during meals at 12-hour intervals. The galenic form to be taken (oral solution or tablets) was defined once at D0 and did not change throughout the study. A maximum of five doses of ivabradine or matching placebo was to be potentially tested in each patient: the doses were adapted every 2 weeks, through a maximum of 4 dose levels, according to the titration rules taking into account the age, the weight, the achievement or not of the HRR target (reduction of at least 20% of baseline HR) and the occurrence or not of bradycardia (HR lower than the predefined HR threshold by age subset) and/or signs or symptoms related to bradycardia.

    Number of subjects in period 1
    Ivabradine Placebo
    Started
    74
    42
    Completed
    61
    28
    Not completed
    13
    14
         Adverse event, serious fatal
    -
    4
         Non medical reason
    -
    1
         Adverse event, non-fatal
    10
    9
         Protocol deviation
    2
    -
         Other protocol withdrawal criteria
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ivabradine
    Reporting group description
    Patients taking Ivabradine

    Reporting group title
    Placebo
    Reporting group description
    Patients taking placebo

    Reporting group values
    Ivabradine Placebo Total
    Number of subjects
    74 42 116
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    18 10 28
        Children (2-11 years)
    43 26 69
        Adolescents (12-17 years)
    13 6 19
    Gender categorical
    Units: Subjects
        Female
    35 17 52
        Male
    39 25 64

    End points

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    End points reporting groups
    Reporting group title
    Ivabradine
    Reporting group description
    Patients taking Ivabradine

    Reporting group title
    Placebo
    Reporting group description
    Patients taking placebo

    Subject analysis set title
    Randomised Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    all patients to whom a therapeutic unit was randomly assigned using IRS.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients having received at least one dose of study drug.

    Subject analysis set title
    Pharmacokinetic Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Consisted of 70 patients in the ivabradine group.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients of the Randomised Set having received at least one dose of study drug, and with at least two evaluations of resting HR: one at baseline, and one post-baseline.

    Subject analysis set title
    Per Protocol Set Titration
    Subject analysis set type
    Per protocol
    Subject analysis set description
    patients of the FAS with one evaluation at baseline, and one evaluation at the end of titration period and having the studied disease, a protocol required background therapy before treatment period, a complete titration period, a correct and sufficient exposure to study drug during the titration period and no major issue in allocation of study drug during the titration period.

    Primary: Target Heart Rate achievement

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    End point title
    Target Heart Rate achievement
    End point description
    the results represent the number of patients who have reached the target Heart Rate.
    End point type
    Primary
    End point timeframe
    D0-End of titration
    End point values
    Ivabradine Placebo
    Number of subjects analysed
    64 [1]
    31 [2]
    Units: number of patients
    46
    5
    Notes
    [1] - Per Protocol Set
    [2] - Per Protocol Set
    Statistical analysis title
    Estimation of treatment effect
    Comparison groups
    Ivabradine v Placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    14.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.79
         upper limit
    46.77
    Notes
    [3] - Estimation of the odds ratio of the target HRR achievement between treatment groups in order to assess the treatment effect

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    D0-M12
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Ivabradine
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Ivabradine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 73 (28.77%)
    17 / 42 (40.48%)
         number of deaths (all causes)
    0
    4
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Heart transplant
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Unintentional medical device removal
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         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
    Pleural effusion
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Cardiovascular evaluation
         subjects affected / exposed
    4 / 73 (5.48%)
    4 / 42 (9.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart rate decreased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcus test positive
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcus test positive
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         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
    Accidental overdose
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrostomy failure
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial flutter
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Low cardiac output syndrome
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Post-traumatic headache
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonic convulsion
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decorticate posture
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         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
    Abdominal lymphadenopathy
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Ischaemic hepatitis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Henoch-Schonlein purpura
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoiditis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 73 (0.00%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoviral upper respiratory infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 42 (2.38%)
         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: 5%
    Non-serious adverse events
    Ivabradine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 73 (86.30%)
    37 / 42 (88.10%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    6 / 73 (8.22%)
    7 / 42 (16.67%)
         occurrences all number
    7
    7
    Cardiovascular evaluation
         subjects affected / exposed
    5 / 73 (6.85%)
    4 / 42 (9.52%)
         occurrences all number
    7
    4
    Heart rate decreased
         subjects affected / exposed
    5 / 73 (6.85%)
    1 / 42 (2.38%)
         occurrences all number
    5
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 73 (6.85%)
    3 / 42 (7.14%)
         occurrences all number
    10
    5
    Accidental overdose
         subjects affected / exposed
    3 / 73 (4.11%)
    3 / 42 (7.14%)
         occurrences all number
    3
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 73 (8.22%)
    3 / 42 (7.14%)
         occurrences all number
    8
    4
    Fatigue
         subjects affected / exposed
    0 / 73 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    5 / 73 (6.85%)
    1 / 42 (2.38%)
         occurrences all number
    5
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 73 (8.22%)
    6 / 42 (14.29%)
         occurrences all number
    6
    7
    Vomiting
         subjects affected / exposed
    6 / 73 (8.22%)
    5 / 42 (11.90%)
         occurrences all number
    7
    6
    Constipation
         subjects affected / exposed
    5 / 73 (6.85%)
    5 / 42 (11.90%)
         occurrences all number
    5
    6
    Abdominal pain
         subjects affected / exposed
    4 / 73 (5.48%)
    3 / 42 (7.14%)
         occurrences all number
    4
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 42 (2.38%)
         occurrences all number
    5
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 73 (21.92%)
    7 / 42 (16.67%)
         occurrences all number
    23
    8
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 73 (12.33%)
    9 / 42 (21.43%)
         occurrences all number
    17
    18
    Bronchitis
         subjects affected / exposed
    10 / 73 (13.70%)
    3 / 42 (7.14%)
         occurrences all number
    13
    4
    Gastroenteritis
         subjects affected / exposed
    9 / 73 (12.33%)
    4 / 42 (9.52%)
         occurrences all number
    10
    6
    Viral infection
         subjects affected / exposed
    7 / 73 (9.59%)
    3 / 42 (7.14%)
         occurrences all number
    11
    5
    Gastroenteritis viral
         subjects affected / exposed
    5 / 73 (6.85%)
    3 / 42 (7.14%)
         occurrences all number
    5
    4
    Respiratory tract infection
         subjects affected / exposed
    4 / 73 (5.48%)
    3 / 42 (7.14%)
         occurrences all number
    4
    6
    Rhinitis
         subjects affected / exposed
    6 / 73 (8.22%)
    1 / 42 (2.38%)
         occurrences all number
    7
    2
    Influenza
         subjects affected / exposed
    4 / 73 (5.48%)
    2 / 42 (4.76%)
         occurrences all number
    5
    3
    Respiratory tract infection viral
         subjects affected / exposed
    3 / 73 (4.11%)
    3 / 42 (7.14%)
         occurrences all number
    6
    3
    Pharyngitis
         subjects affected / exposed
    5 / 73 (6.85%)
    0 / 42 (0.00%)
         occurrences all number
    10
    0
    Otitis media
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 42 (2.38%)
         occurrences all number
    7
    1
    Laryngitis
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 42 (0.00%)
         occurrences all number
    4
    0
    Pneumonia
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    Tonsillitis
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    Ear infection
         subjects affected / exposed
    5 / 73 (6.85%)
    0 / 42 (0.00%)
         occurrences all number
    8
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 73 (2.74%)
    4 / 42 (9.52%)
         occurrences all number
    2
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2011
    The objective of this amendment was to comply with local requirements of the French Medicine Agency (AFSSAPS) renamed recently as Agence Nationale de Sécurité du Médicament et des produits de la Santé (ANSM) for the implementation of the CL2-16257-090 clinical trial in France. The following modifications were proposed: The addition in the non-selection criteria list that contraception was required in girls with childbearing potential and sexually active. The addition as a withdrawal criterion for the girls that were unwillingness to use a contraceptive method with a childbearing potential and sexually active. The reporting of the occurrence of any visual adverse event. In case of visual adverse event occurrence, the investigator had to schedule a visit with an ophthalmologist to characterize the symptoms and have an advice for management. The parents and legal representative information and consent/assent forms were amended.
    14 Feb 2012
    The objective of this amendment was to comply with the need for clarification, the requirements and the recommendations of the Regulatory Authorities, Ethics Committees and International Scientific Board for the implementation of the CL2-16257-090 clinical trial internationally.
    22 May 2012
    was applicable to all centres in Germany. The objective of this amendment was to comply with the need for clarification, the requirements and the recommendations of the Berlin Ethics Committee (EC) for the implementation of the CL2-16257-090 study in Germany. At the time of the review of the initial protocol by the Berlin EC the first international amendment No. 2 had been issued (the amendment No. 1 was applicable only for France). The current local amendment took into consideration the changes made by the Amendment No. 2
    07 Sep 2012
    was applicable in all countries. It concerned mainly: The update information on concomitant treatments to be used with precaution during the study: potassium-depleting diuretics should be used with precaution according to the modification of the Summary of Product Characteristics, The update of the list of adverse events for which specific information was requested and already collected. The parents and legal representative information and consent/assent forms were also amended with the addition of the new undesirable effect (abnormal ECG heart tracing). This amendment did not require any changes to the patient assent forms.
    22 Nov 2012
    was applicable to all centres in all countries. It concerned administrative changes.
    23 May 2013
    Was applicable in all countries. The objectives were : - to defer the planned study completion date and to update the number of patients to be recruited by age-subset - to update the protocol in accordance with the DSMB recommendations concerning patients with QTcB>450 ms.

    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.
    The section NSAE presented EAEs on treatment and included SEAEs. The causality and seriousness of reported SAE can be ultimately upgraded by the sponsor. The sponsor took these decisions to be compliant with the existing ICH E3 Clinical Study Report
    For support, Contact us.
    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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