Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

  • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).


    The EU Clinical Trials Register currently displays   44054   clinical trials with a EudraCT protocol, of which   7319   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).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Safety of oral chronic administration of ivabradine modified release formulation compared to ivabradine immediate release formulation, in patients with stable coronary artery disease. A 6 to 12-month randomised double blind parallel groups multicentre study

    Summary
    EudraCT number
    2012-001668-31
    Trial protocol
    GB   HU   DE   SK   NL   ES   BG   IT  
    Global end of trial date
    14 Apr 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jul 2016
    First version publication date
    02 Aug 2015
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CL3-16257-097
    Additional study identifiers
    ISRCTN number
    -
    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
    ITP ( Innovation Therapeutic Pole), Institut de Recherches Internationales Servier, 33 155.72.43.66, clinicaltrials@servier.com
    Scientific contact
    ITP ( Innovation Therapeutic Pole), Institut de Recherches Internationales Servier, 33 155.72.43.66, clinicaltrials@servier.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
    14 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the safety profiles of the ivabradine modified release (MR) formulation and ivabradine immediate release (IR) formulation over a 6-month period
    Protection of trial subjects
    Study treatment could be prematurely and definitively discontinued by the investigator for any of the following reasons: Study drug not tolerated: occurrence of suspected adverse drug reaction that cause discomfort to the patient, led to interruption of usual activities, or was considered by the investigator as a safety issue (e.g. significant symptoms of low HR or HR < 50 bpm on the lowest study treatment doses). Study drug no longer appropriated (e.g. permanent atrial fibrillation). Study drug considered as contraindicated (e.g. pregnancy, sick sinus syndrome or concomitant administration of a strong cytochrome P450 3A4 inhibitor). Unwillingness of the patient to continue with the study. In case the investigator had no news of a patient, he/she had to make every effort to contact him/her (unless the patient withdrew her/his consent), to obtain the date and the reason for discontinuation, to kindly ask the patient to resume the study procedures or at least come for an end-of-study visit. If all attempts failed, the investigator declared the patient “lost to follow-up”. All actions implemented were documented in the corresponding medical file
    Background therapy
    Standard guideline recommended
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Nov 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 83
    Country: Number of subjects enrolled
    Vietnam: 40
    Country: Number of subjects enrolled
    Korea, Republic of: 72
    Country: Number of subjects enrolled
    Netherlands: 91
    Country: Number of subjects enrolled
    Slovakia: 51
    Country: Number of subjects enrolled
    Spain: 107
    Country: Number of subjects enrolled
    United Kingdom: 58
    Country: Number of subjects enrolled
    Bulgaria: 117
    Country: Number of subjects enrolled
    Germany: 59
    Country: Number of subjects enrolled
    Hungary: 119
    Country: Number of subjects enrolled
    Italy: 45
    Worldwide total number of subjects
    842
    EEA total number of subjects
    647
    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)
    479
    From 65 to 84 years
    360
    85 years and over
    3

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    - Women or men; - Age ≥ 18 years; - Documented stable CAD with or without chronic stable angina pectoris; . In stable condition for at least 1 month before selection with regards to clinical symptoms and cardiovascular treatments - Normal sinus rhythm; - Resting heart rate ≥ 60bpm.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ivabradine MR
    Arm description
    6-month treatment period in the SS.
    Arm type
    Experimental

    Investigational medicinal product name
    Ivabradine MR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    During the randomised double-blind treatment period, patients received the study treatment (either ivabradine MR or IR and a placebo capsule or tablet), which were taken orally twice daily, at 12-hour intervals in the morning (one capsule and one tablet) and the evening (one tablet) during meals. The starting dose of ivabradine or matching placebo was MR 15 mg o.d. / IR 5 mg b.i.d. at D0. At the subsequent follow-up visits, the study treatment was either maintained at the current dose, or increased in dose or reduced in dose or discontinued, depending on the patient’s ECG resting HR and tolerability.

    Arm title
    Ivabradine IR
    Arm description
    6-month treatment period in the SS.
    Arm type
    Active comparator

    Investigational medicinal product name
    Ivabradine IR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the randomised double-blind treatment period, patients received the study treatment (either ivabradine MR or IR and a placebo capsule or tablet), which were taken orally twice daily, at 12-hour intervals in the morning (one capsule and one tablet) and the evening (one tablet) during meals. The starting dose of ivabradine or matching placebo was MR 15 mg o.d. / IR 5 mg b.i.d. at D0. At the subsequent follow-up visits, the study treatment was either maintained at the current dose, or increased in dose or reduced in dose or discontinued, depending on the patient’s ECG resting HR and tolerability.

    Number of subjects in period 1
    Ivabradine MR Ivabradine IR
    Started
    421
    421
    Completed
    351
    371
    Not completed
    70
    50
         Other protocol withdrawal critéria
    -
    1
         Adverse event
    41
    36
         Lost to follow-up
    1
    -
         Non-medical reason
    19
    11
         Protocol deviation
    9
    2

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    -

    Reporting group values
    Overall study Total
    Number of subjects
    842 842
    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)
    479 479
        From 65-84 years
    360 360
        85 years and over
    3 3
    Gender categorical
    Units: Subjects
        Female
    206 206
        Male
    636 636

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Ivabradine MR
    Reporting group description
    6-month treatment period in the SS.

    Reporting group title
    Ivabradine IR
    Reporting group description
    6-month treatment period in the SS.

    Primary: Emergent adverse events

    Close Top of page
    End point title
    Emergent adverse events [1]
    End point description
    The primary objective was the safety assessment over the first 6 months.
    End point type
    Primary
    End point timeframe
    the first 6 months.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Emergent adverse events have been analysed using descriptive statistics
    End point values
    Ivabradine MR Ivabradine IR
    Number of subjects analysed
    419
    421
    Units: Number of affected patients
    240
    265
    No statistical analyses for this end point

    Primary: Emergent adverse events in the angina patients subgroup

    Close Top of page
    End point title
    Emergent adverse events in the angina patients subgroup [2]
    End point description
    Safety assessment over the first 6 months of treatment in the Angina patients subgroup.
    End point type
    Primary
    End point timeframe
    the first 6 months of treatment
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Emergent adverse events have been analysed using descriptive statistics
    End point values
    Ivabradine MR Ivabradine IR
    Number of subjects analysed
    253
    245
    Units: Number of affected patients
    142
    150
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Overall study
    Adverse event reporting additional description
    The first 6-month treatment period (main analysis) was followed by a blinded extension treatment period of 6 months for early recruited eligible patients in each group. Therefore,In the following reporting groups, patients in the Ivabradine MR 12-month group were also in the Ivabradine MR 6-month group (same thing for Ivabradine IR groups).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    Ivabradine MR first 6-month period
    Reporting group description
    -

    Reporting group title
    Ivabradine IR first 6-month period
    Reporting group description
    -

    Reporting group title
    Ivabradine MR 12 months
    Reporting group description
    -

    Reporting group title
    Ivabradine IR 12 months
    Reporting group description
    -

    Serious adverse events
    Ivabradine MR first 6-month period Ivabradine IR first 6-month period Ivabradine MR 12 months Ivabradine IR 12 months
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 419 (12.89%)
    69 / 421 (16.39%)
    25 / 140 (17.86%)
    29 / 130 (22.31%)
         number of deaths (all causes)
    3
    3
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 419 (0.24%)
    1 / 421 (0.24%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma stage II
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to heart
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer stage 0
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 419 (0.24%)
    8 / 421 (1.90%)
    1 / 140 (0.71%)
    4 / 130 (3.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 8
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 419 (0.24%)
    1 / 421 (0.24%)
    1 / 140 (0.71%)
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood pressure inadequately controlled
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cardiac rehabilitation therapy
         subjects affected / exposed
    1 / 419 (0.24%)
    3 / 421 (0.71%)
    0 / 140 (0.00%)
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neck operation
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery bypass
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cranioplasty
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric bypass
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc operation
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Percutaneous coronary intervention
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    2 / 140 (1.43%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rehabilitation therapy
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sympathetic nerve destruction
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    chest pain
         subjects affected / exposed
    1 / 419 (0.24%)
    1 / 421 (0.24%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 419 (0.48%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    2 / 419 (0.48%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Impaired driving ability
         subjects affected / exposed
    1 / 419 (0.24%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 419 (0.24%)
    2 / 421 (0.48%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 419 (0.48%)
    1 / 421 (0.24%)
    1 / 140 (0.71%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 419 (0.00%)
    2 / 421 (0.48%)
    1 / 140 (0.71%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigation
         subjects affected / exposed
    0 / 419 (0.00%)
    2 / 421 (0.48%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angiogram
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriogram coronary
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular evaluation
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagogastroduodenoscopy
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 419 (0.48%)
    2 / 421 (0.48%)
    0 / 140 (0.00%)
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery restenosis
         subjects affected / exposed
    2 / 419 (0.48%)
    1 / 421 (0.24%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia postoperative
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone fissure
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    3 / 419 (0.72%)
    5 / 421 (1.19%)
    2 / 140 (1.43%)
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 419 (0.72%)
    6 / 421 (1.43%)
    3 / 140 (2.14%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    3 / 419 (0.72%)
    5 / 421 (1.19%)
    0 / 140 (0.00%)
    3 / 130 (2.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    4 / 419 (0.95%)
    2 / 421 (0.48%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 419 (0.72%)
    2 / 421 (0.48%)
    1 / 140 (0.71%)
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 419 (0.48%)
    2 / 421 (0.48%)
    1 / 140 (0.71%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 419 (0.24%)
    2 / 421 (0.48%)
    1 / 140 (0.71%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 419 (0.24%)
    2 / 421 (0.48%)
    1 / 140 (0.71%)
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 419 (0.24%)
    1 / 421 (0.24%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 419 (0.24%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    1 / 140 (0.71%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 419 (0.24%)
    3 / 421 (0.71%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 419 (0.24%)
    3 / 421 (0.71%)
    2 / 140 (1.43%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 419 (0.00%)
    2 / 421 (0.48%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral atrophy
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuritis
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular headache
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Normochromic normocytic anaemia
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Photopsia
         subjects affected / exposed
    3 / 419 (0.72%)
    2 / 421 (0.48%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 419 (0.24%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choroidal detachment
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choroidal haemorrhage
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal disorder
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinopathy hypertensive
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous detachment
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum intestinal
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Defaecation urgency
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenitis haemorrhagic
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis atopic
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal artery stenosis
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 419 (0.24%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 419 (0.24%)
    1 / 421 (0.24%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 419 (0.24%)
    0 / 421 (0.00%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 419 (0.00%)
    0 / 421 (0.00%)
    1 / 140 (0.71%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 419 (0.00%)
    2 / 421 (0.48%)
    0 / 140 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 419 (0.00%)
    1 / 421 (0.24%)
    0 / 140 (0.00%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ivabradine MR first 6-month period Ivabradine IR first 6-month period Ivabradine MR 12 months Ivabradine IR 12 months
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    240 / 419 (57.28%)
    265 / 421 (62.95%)
    93 / 140 (66.43%)
    97 / 130 (74.62%)
    Investigations
    Heart rate decreased
         subjects affected / exposed
    30 / 419 (7.16%)
    21 / 421 (4.99%)
    12 / 140 (8.57%)
    7 / 130 (5.38%)
         occurrences all number
    30
    22
    12
    7
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 419 (5.25%)
    33 / 421 (7.84%)
    12 / 140 (8.57%)
    15 / 130 (11.54%)
         occurrences all number
    23
    34
    12
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 419 (1.91%)
    19 / 421 (4.51%)
    1 / 140 (0.71%)
    9 / 130 (6.92%)
         occurrences all number
    9
    19
    1
    9
    Eye disorders
    Photopsia
         subjects affected / exposed
    44 / 419 (10.50%)
    29 / 421 (6.89%)
    14 / 140 (10.00%)
    12 / 130 (9.23%)
         occurrences all number
    46
    32
    15
    14
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    15 / 419 (3.58%)
    12 / 421 (2.85%)
    9 / 140 (6.43%)
    8 / 130 (6.15%)
         occurrences all number
    15
    12
    9
    8

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Nov 2012
    Amendment No. 1, dated 29 November 2012, was applicable in Argentina. To comply with local requirements of the Medicine Agency of Argentina - ANMAT (Administración Nacional de Medicamentos, Alimentos y Tecnología Médica) for the implementation of the clinical trial in Argentina, a pregnancy test at the beginning of the study and at every patient visit for women with childbearing potential was added. Finally, due to dynamic recruitment in other participating countries together with regulatory timelines, there were no Argentinian centres opened for participation in this study.
    29 Apr 2013
    Amendment No. 2, dated 29 April 2013, concerned all investigational sites in all countries. The main changes were: Following the European Medicine Agency scientific advice (issued on the 17th of January 2013):  Given the importance of clinical data on the ivabradine IR and MR formulations switch, the number of patients evaluated in the setting of 3-month switch period was increased from 60 to 120 in each treatment arm.  Patient’s background treatment (in particular beta-blockers) at the time of formulation switch was collected. In order to reach the target of 120 patients for PK assessment, the total number of patients planned to be evaluated was increased from 700 up to approximately 850. Documentation of events of special interest for ivabradine (bradycardia, ECG prolonged QT interval, eye disorders, rhythm and conduction disorders, increase in blood pressure in hypertensive patients, immune disorders) was detailed, in order to harmonise the study protocol with the latest proposed version of the EU-Risk Management Plan (RMP) of ivabradine hydrochloride (issued on the 22nd of January 2013). The amendment also included diverse adaptations to improve the study patient’s follow-up by the investigators, spelling corrections.

    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 ClinicalStudy 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.

    European Medicines Agency © 1995-Thu Sep 19 11:53:52 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA