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    Clinical Trial Results:
    Effects of oral chronic administration of ivabradine (7.5 mg b.i.d.) in comparison to placebo (b.i.d.) on top of beta-blockers, on central aortic blood pressure. Randomised, cross-over, double-blind, multicentre, study over 10 weeks in patients with stable coronary artery disease and a resting heart rate equal or superior to 70 bpm, already treated with beta-blockers.

    Summary
    EudraCT number
    		 2011-004779-35
    Trial protocol
    		 IE   IT  
    Global end of trial date
    13 May 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-16257-096
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Therapeutic Innovation Pole, Institut de Recherches Internationales Servier, 33 155724366, clinicaltrials@servier.com
    Scientific contact
    Therapeutic Innovation Pole, Institut de Recherches Internationales Servier, 33 155724366, 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
    13 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the effect of ivabradine on central aortic systolic blood pressure (CASBP) in comparison to placebo in patients with stable coronary artery disease (CAD), and a resting heart rate (HR) ≥ 70 bpm, treated by beta-blockers (BBs).
    Protection of trial subjects
    Non-selection criteria: -Pregnant women, breast-feeding or women of childbearing potential not using, oestro-progestative or progestative or intra-uterine contraception or subcutaneous contraceptive implant, or using oestro-progestative or progestative or intra-uterine contraception or subcutaneous contraceptive implant but who consider stopping it during the duration of the study -History of central neuropathy and/or of symptomatic orthostatic hypotension of nonmedicamentous etiology -Severe hypotension at the time of selection (blood pressure < 90 / 50 mmHg) -Patient currently or previously treated with ivabradine within the last 3 months before selection visit -Patient currently or previously treated with nebivolol within the last 3 months before selection visit -Patients with recent (less than 3 months) MI or coronary revascularisation -Patients with recent (less than 3 months) stroke or cerebral transient ischemic attack -Patients scheduled for coronary revascularisation procedures -Patients with transplanted heart -Implanted pacemaker, implantable cardioverter defibrillator, cardiac resynchronisation therapy -Valvular disease likely to require surgery within the coming year -Permanent atrial fibrillation or flutter -Sick sinus syndrome, sino-atrial block, congenital long QT, 2nd degree and complete atrio-ventricular block -Patients with angina at rest and angina of class IV -Clinical signs and/or symptoms of heart failure in NYHA class II or higher -Hospitalisation for heart failure as primary diagnosis within the last 12 months -Known carriers of hepatitis B surface antigen or human immunodeficiency virus antibodies or hepatitis C virus antibodies -Known alcohol or drug abuse -Patients requiring treatments which are not allowed during the study -Known hypersensitivity or contra-indication to the administration of ivabradine -Known hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
    Background therapy
    		 Beta-blockers at doses estimated appropriate by the investigators.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jun 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    9
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Males and females (at least 30 years old) with medical history of CAD, with sinus rhythm, stable and appropriate treatment by beta blockers at the exception of nebivolol and carvedilol, with sinus rhythm and 12-lead ECG HR ≥ 70 bpm at selection and at inclusion visit, with normal fasting laboratory results and informed consent obtained.

    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
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ivabradine/Placebo
    Arm description
    		 - 3-week double-blind active treatment period P1: patients received Ivabradine - 2-week wash-out period: patients received no study treatment - 3-week double-blind active treatment period P2: patients received Placebo
    Arm type
    		 Test drug

    Investigational medicinal product name
    Ivabradine
    Investigational medicinal product code
    S16257
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    7.5 mg tablets twice a day at 12-hour intervals during meals, at breakfast and dinner, starting the next morning at breakfast after the visit.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matched tablets twice a day during meals, at breakfast and at dinner, starting the next morning after the visit.

    Arm title
    		 Placebo/Ivabradine
    Arm description
    		 - 3-week double-blind active treatment period P1: patients received Placebo - 2-week wash-out period: patients received no study treatment - 3-week double-blind active treatment period P2: patients received Ivabradine
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matched tablets twice a day during meals, at breakfast and at dinner, starting the next morning after the visit.

    Investigational medicinal product name
    Ivabradine
    Investigational medicinal product code
    S16257
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    7.5 mg tablets twice a day at 12-hour intervals during meals, at breakfast and dinner, starting the next morning at breakfast after the visit.

    Number of subjects in period 1
    		Ivabradine/Placebo Placebo/Ivabradine
    Started
    6
    8
    Completed
    6
    6
    Not completed
    0
    2
         Adverse event, non-fatal
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ivabradine/Placebo
    Reporting group description
    		 - 3-week double-blind active treatment period P1: patients received Ivabradine - 2-week wash-out period: patients received no study treatment - 3-week double-blind active treatment period P2: patients received Placebo

    Reporting group title
    Placebo/Ivabradine
    Reporting group description
    		 - 3-week double-blind active treatment period P1: patients received Placebo - 2-week wash-out period: patients received no study treatment - 3-week double-blind active treatment period P2: patients received Ivabradine

    Reporting group values
    		 Ivabradine/Placebo Placebo/Ivabradine Total
    Number of subjects
    		 6 8 14
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 2 7 9
        From 65-84 years
    		 4 1 5
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69 ± 7.8 58.4 ± 5.9 -
    Gender categorical
    Units: Subjects
        Female
    		 1 1 2
        Male
    		 5 7 12

    End points

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    End points reporting groups
    Reporting group title
    Ivabradine/Placebo
    Reporting group description
    		 - 3-week double-blind active treatment period P1: patients received Ivabradine - 2-week wash-out period: patients received no study treatment - 3-week double-blind active treatment period P2: patients received Placebo

    Reporting group title
    Placebo/Ivabradine
    Reporting group description
    		 - 3-week double-blind active treatment period P1: patients received Placebo - 2-week wash-out period: patients received no study treatment - 3-week double-blind active treatment period P2: patients received Ivabradine

    Subject analysis set title
    Ivabradine
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) consisted of 9 patients

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) consisted of 9 patients

    Primary: CASBP-change from baseline over 3-week treatment period

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    End point title
    		 CASBP-change from baseline over 3-week treatment period [1]
    End point description
    Change of central aortic systolic blood pressure from baseline.
    End point type
    Primary
    End point timeframe
    Change from baseline over 3-week treatment period
    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: Due to recruitment issues, the study was prematurely stopped after 14 patients were included. Therefore only descriptive statistics will be performed.
    End point values
    		 Ivabradine Placebo
    Number of subjects analysed
    9
    9
    Units: mmHg
        arithmetic mean (standard deviation)
    -3.3 ± 10.2
    1 ± 9.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE occuring during treatment periods only.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    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
    0 / 12 (0.00%)
    1 / 14 (7.14%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Coronary artery restenosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 14 (7.14%)
         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
    4 / 12 (33.33%)
    2 / 14 (14.29%)
    Injury, poisoning and procedural complications
    Coronary artery restenosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Photopsia
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 14 (0.00%)
         occurrences all number
    4
    0
    Retinal disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Night sweats
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Sep 2012
    This amendment will apply to the centers in FRANCE, IRELAND and ITALY: - Precision on CAD and Type II diabetes documentation. - Addition of carvedilol to not allowed previous beta-blocker treatment. Addition of substance-induced long QT as medical and therapeutic non-selection criterion. - Addition of carvedilol to not allowed previous beta-blocker treatments. - Addition of potassium-depleting diuretics as treatment to be used with precautions in patients receiving ivabradine and having long QT interval. Addition of carvedilol and marketed ivabradine to not allowed concomitant treatments. - Precision on tonometry methods (dominant arm) - Precision on blood pressure measurement (dominant arm) - Update the list of adverse events for wich specific information is requested and already collected.
    26 Mar 2013
    This amendment will apply to the centers in FRANCE, IRELAND and ITALY: The main changes are: - The removal of the type II diabetes selection criteria. - The change of the planned date of Last Visit Last Patient - The addition of a non-inclusion criterion related to the quality of applanation tonometry at inclusion visit.
    03 Jul 2013
    This amendment will apply to the centers in FRANCE, IRELAND and ITALY: The main changes are: - The addition of a new participating Country/Centre in Italy and the possibility to set-up a new centre, not yet identified, in France - The modification of titles of sponsor signatories - The measurement of skin capillary density only in patients from centres equipped with the adequate material - The addition of non-selection and non-inclusion criteria related to the type and to the stability of diabetes before selection.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 May 2014
    The study was prematurely stopped due to recruitment issue.
    -

    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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