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    Clinical Trial Results:
    Effects of ivabradine on vascular function in individuals at increased risk of developing cardiovascular disease and with impaired endothelial function An international, multicentre, randomised, double-blind, placebo-controlled study over 12 weeks.

    Summary
    EudraCT number
    		 2012-000215-89
    Trial protocol
    		 IT   GB   NL  
    Global end of trial date
    18 Apr 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
    CL2-16257-099
    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, France, 92284
    Public contact
    Therapeutic Innovation Pole, Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Therapeutic Innovation 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
    18 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    ­To demonstrate the beneficial effect of ivabradine compared with placebo on endothelial function as measured by flow mediated dilation (FMD) of the brachial artery at 12 weeks of treatment
    Protection of trial subjects
    Before randomisation, a patient was to be withdrawn from the study when the investigator was aware that a selection/non-selection criterion or an inclusion/non-inclusion criterion was not verified. The IMP was prematurely discontinued in the following circumstances: -IMP not tolerated: occurrence of any suspected adverse reaction that caused the patient discomfort and led to interruption of usual activities or in the case of a suspected adverse reaction that was considered by the investigator as a safety issue. An example of such a situation could be the occurrence or persistence of symptomatic bradycardia while the lower IMP dose-regimen (ivabradine 5 mg bid or matching placebo) was administered. -IMP no longer appropriate: occurrence of prolonged loss of sinus rhythm (for example persistent atrial fibrillation). -IMP considered as contra-indicated: e.g. sick sinus syndrome or sino-atrial block. -Need of treatment not allowed during the study: e.g. strong CYP3A4 inhibitor. -Major protocol deviation which, in the opinion of the investigator, made it unsafe for the patient to continue to take the test drug and to stay in the study. -Non-medical reason: e.g. patient’s personal decision to stop treatment, withdrawal of consent etc… -Lost to follow-up: when the investigator had no news of the participant, he/she made every effort to contact him/her, to establish the reason for the discontinuation of treatment, and to suggest the participant came to an end-of-study visit. If all these attempts to contact the participant failed, the investigator was to declare the participant “lost to follow-up”. The investigator documented all these attempts in the corresponding medical file.
    Background therapy
    		 The treatment received by the study participants should be optimal according to the investigator’s judgement and in accordance to guidelines
    Evidence for comparator
    		 Placebo
    Actual start date of recruitment
    06 Dec 2013
    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
    Netherlands: 1
    Country: Number of subjects enrolled
    Germany: 3
    Worldwide total number of subjects
    4
    EEA total number of subjects
    4
    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)
    3
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 15 centres were "opened" and trained. Only 10 centres in DEU and NLD screened patients (total of 53 patients) 9 patients were selected (5 in DEU and 4 in NLD). A total of 4 patients were included and randomly assigned: 2 in the ivabradine group and 2 in the placebo group. No patient completed the study since it was terminated prematurely

    Pre-assignment
    Screening details
    		 Men or postmenopausal women aged 21-74 years, in sinus rhythm with resting HR superior or equal to 75 bpm, at increased risk of subsequent cardiovascular disease (documented by the presence of at least two cardiovascular risk factors such as diabetes, hypertension, smoking, hypercholesterolemia) and impaired FMD (<5.0%), signed an informed consent

    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
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ivabradine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the treatment period after randomisation, the IMP (double-blind ivabradine or matching placebo) was taken orally twice daily, at 12-hour intervals in the morning and in the evening, during meals. Three doses were used: 5 mg, 7.5 mg or 10 mg tablets ivabradine or matching placebo.

    Arm title
    		 Placebo
    Arm description
    		 -
    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
    During the treatment period after randomisation, the IMP (double-blind ivabradine or matching placebo) was taken orally twice daily, at 12-hour intervals in the morning and in the evening, during meals. Three doses were used: 5 mg, 7.5 mg or 10 mg tablets ivabradine or matching placebo.

    Number of subjects in period 1
    		Ivabradine Placebo
    Started
    2
    2
    Completed
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    		 -

    Reporting group values
    		 Overall study Total
    Number of subjects
    		 4 4
    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)
    		 3 3
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 2 2
    Subject analysis sets

    Subject analysis set title
    Randomised Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    No statistical analysis plan was written because of the small sample size.

    Subject analysis sets values
    		 Randomised Set
    Number of subjects
    4
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    3
        From 65-84 years
    1
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    2
        Male
    2

    End points

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    End points reporting groups
    Reporting group title
    Ivabradine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Randomised Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    No statistical analysis plan was written because of the small sample size.

    Primary: No primary endpoint

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    End point title
    		 No primary endpoint [1]
    End point description
    The primary endpoint was the absolute percentage change in FMD of the brachial artery from baseline to 12 weeks for ivabradine compared with placebo. However, because of the premature study termination, no FMD was performed under or after treatment intake.
    End point type
    Primary
    End point timeframe
    The primary endpoint was the absolute percentage change in FMD of the brachial artery from baseline to 12 weeks for ivabradine compared with placebo. However, because of the premature study termination, no FMD was performed under or after treatment intake
    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: The primary endpoint was the absolute percentage change in FMD of the brachial artery from baseline to 12 weeks for ivabradine compared with placebo. However, because of the premature study termination, no FMD was performed under or after treatment intake.
    End point values
    		 Ivabradine Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: not applicable
    Notes
    [2] - Because of the premature study termination, no FMD was performed under or after treatment intake.
    [3] - Because of the premature study termination, no FMD was performed under or after treatment intake.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    the overall study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Ivabradine
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Ivabradine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Ivabradine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Feb 2014
    Amendment No. 1, dated 28 February 2014, was applicable in all countries. It concerned mainly: The modification of the study selection criteria to allow the inclusion of patients with “minor and stable cardiovascular disease” (the HR requirement of ≥ 75 bpm was left unchanged). The minimal time between selection and inclusion visits is reduced from 12 to 6 days. The amendment did not require any changes to the patient information sheet or informed consent form.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Apr 2014
    Decision to prematurely terminate the study The study investigators were informed by letter (dated 07-Apr-2014) of the decision to end the study. At the end of March 2014, I.R.I.S., in agreement with the Scientific Board, took the decision to prematurely discontinue this study in view of the difficulties in the recruitment process and the strategic objectives for ivabradine.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    At the end of March 2014, I.R.I.S., in agreement with the Scientific Board, took the decision to prematurely discontinue this study in view of the difficulties in the recruitment process and the strategic objectives for ivabradine.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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