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    Clinical Trial Results:
    A randomized, double blind, placebo-controlled, parallel, international multicenter study assessing the efficacy of S 066913 in patients with paroxysmal atrial fibrillation Double-blind, International study AssessinG efficacy of S 066913 in paRoxysmal Atrial Fibrillation – IKur inhibitor (DIAGRAF - IKUR).

    Summary
    EudraCT number
    2014-002333-63
    Trial protocol
    CZ   SK   SE   DK   NL   PL  
    Global end of trial date
    06 Sep 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Jun 2017
    First version publication date
    02 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-066913-002
    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
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 0155724366, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 0155724366, 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
    06 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Evaluation of the efficacy of three doses of S 66913 (5 mg, 25 mg and 100 mg o.d.) versus placebo administered for 4 weeks, on atrial fibrillation and/or atrial tachycardia burden (AF/AT burden) in patients with paroxysmal atrial fibrillation (PAF) who were potentially eligible for atrial fibrillation (AF) ablation and were implanted with insertable continuous cardiac rhythm monitoring (ICM) device. The study was divided into 3 periods: A pre-randomisation baseline period (Period 1) of at least 4 weeks during which the ICM was implanted and the eligibility according to ICM data and blood test results was assessed. A double-blind treatment period lasting 4 weeks (Period 2). A post-treatment and extended follow-up period (appears here as part of Period 2 for technical reasons) comprising visits WEND, FU1 and FU2 (6 months after FU1).
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Dec 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Slovakia: 1
    Worldwide total number of subjects
    58
    EEA total number of subjects
    35
    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)
    40
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Investigators were cardiologists having expertise in arrhythmology.

    Pre-assignment
    Screening details
    The patients were adult male or female (non-childbearing potential), in sinus rhythm at selection visit, with at least one AF episode within the last 18 months and at least 2 other AF episodes within 30 days, prior to selection visit, indicated for AF ablation and eligible for ICM implantation (or having an approved ICM device).

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    All patients
    Arm description
    -
    Arm type
    ICM

    Investigational medicinal product name
    No IMP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Implant, Transdermal system
    Routes of administration
    Implantation
    Dosage and administration details
    Insertable Continuous Monitoring (ICM) implantation .

    Number of subjects in period 1
    All patients
    Started
    58
    Completed
    58
    Period 2
    Period 2 title
    DB treatment period + extended FU
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    The study was double-blinded with active drugs and matching placebo supplied as identical tablets and packaging.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    S 66913 5 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    S 66913 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The treatment consisted of 3 tablets (2 big and 1 small, either could contain S 66913 5 mg or placebo) administered orally once daily during breakfast i.e. visually identical for each treatment arm.

    Arm title
    S 66913 25 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    S 66913 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The treatment consisted of 3 tablets (2 big and 1 small, either could contain S 66913 12.5 mg or placebo) administered orally once daily during breakfast i.e. visually identical for each treatment arm.

    Arm title
    S 66913 100 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    S 66913 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The treatment consisted of 3 tablets (2 big and 1 small, either could contain S 66913 50 mg or placebo) administered orally once daily during breakfast i.e. visually identical for each treatment arm.

    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
    The treatment consisted of 3 tablets (2 big and 1 small) administered orally once daily during breakfast i.e. visually identical for each treatment arm.

    Number of subjects in period 2
    S 66913 5 mg S 66913 25 mg S 66913 100 mg Placebo
    Started
    16
    13
    15
    14
    Completed
    10
    11
    11
    11
    Not completed
    6
    2
    4
    3
         Other
    1
    -
    -
    -
         Study discontinuation
    5
    1
    4
    3
         Protocol deviation
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All patients
    Reporting group description
    -

    Reporting group values
    All patients Total
    Number of subjects
    58 58
    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)
    40 40
        From 65-84 years
    18 18
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.5 ( 10.2 ) -
    Gender categorical
    Units: Subjects
        Female
    16 16
        Male
    42 42
    AF/AT Burden
    Units: percent
        median (inter-quartile range (Q1-Q3))
    9.6 (2.7 to 20.4) -

    End points

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    End points reporting groups
    Reporting group title
    All patients
    Reporting group description
    -
    Reporting group title
    S 66913 5 mg
    Reporting group description
    -

    Reporting group title
    S 66913 25 mg
    Reporting group description
    -

    Reporting group title
    S 66913 100 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    In accordance with the intention-to-treat principle, all patients of the Randomized Set having taken at least one dose of IMP and with at least two evaluations of AF/AT burden on adjudicated data from ICM: one over baseline period and one over 4-week treatment period.

    Primary: AF/AT Burden

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    End point title
    AF/AT Burden [1]
    End point description
    The primary efficacy endpoint was the AF/AT burden derived from ICM device recording, expressed mainly as absolute change from baseline over the 4-week treatment period.
    End point type
    Primary
    End point timeframe
    The AF/AT burden is calculated as the percentage time in AF and/or AT (including atrial flutter (AFL)) during the total observation 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: Prematurely discontinued study treatment as a precautionary measure due to a non-clinical safety concern.
    End point values
    S 66913 5 mg S 66913 25 mg S 66913 100 mg Placebo
    Number of subjects analysed
    15
    13
    14
    14
    Units: percent
        median (inter-quartile range (Q1-Q3))
    0.1 (-1.4 to 2.3)
    0.5 (-4.4 to 1.8)
    -0.3 (-3.1 to 0.5)
    0.7 (-2.1 to 6.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Double-blind 4 weeks period (W0-W4) for each group and post-treatment/extended follow-up period for patients who took at least one dose of study drug. For FU, contact was established for 51 patients: 39 attended FU1; 37 attended FU2.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    S 66913 5 mg
    Reporting group description
    -

    Reporting group title
    S 66913 25 mg
    Reporting group description
    -

    Reporting group title
    S 66913 100 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    FU after starting with S 66913 5 mg
    Reporting group description
    -

    Reporting group title
    FU after starting with S 66913 25 mg
    Reporting group description
    -

    Reporting group title
    FU after starting with S 66913 100 mg
    Reporting group description
    -

    Reporting group title
    FU after starting with Placebo
    Reporting group description
    -

    Serious adverse events
    S 66913 5 mg S 66913 25 mg S 66913 100 mg Placebo FU after starting with S 66913 5 mg FU after starting with S 66913 25 mg FU after starting with S 66913 100 mg FU after starting with Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    3 / 14 (21.43%)
    2 / 11 (18.18%)
    2 / 14 (14.29%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Vitreous adhesions
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    S 66913 5 mg S 66913 25 mg S 66913 100 mg Placebo FU after starting with S 66913 5 mg FU after starting with S 66913 25 mg FU after starting with S 66913 100 mg FU after starting with Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 16 (31.25%)
    1 / 13 (7.69%)
    1 / 14 (7.14%)
    3 / 14 (21.43%)
    3 / 14 (21.43%)
    2 / 11 (18.18%)
    3 / 14 (21.43%)
    3 / 12 (25.00%)
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Investigations
    Electrocardiogram PR prolongation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    International normalised ratio fluctuation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Vital capacity decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Functional residual capacity increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Carbon monoxide diffusing capacity decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Total lung capacity decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Expiratory reserve volume increased
    Additional description: Residual volume of the lungs increased.
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Pericarditis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Atrial thrombosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Phrenic nerve paralysis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Facial paralysis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Gingival recession
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash pruritic
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Cystitis escherichia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    1
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Oct 2014
    Amendment n°1 applicable in all countries: modification of selection criterion 1 regarding the inclusion of women of childbearing potential who were to be excluded. A pregnancy test was therefore no longer appropriate and birth control method was updated.
    27 Jan 2015
    Amendment n°3 applicable in all countries: interdiction of rosuvastatin (a BCRP substrate) as a precautionary measure.
    03 Jul 2015
    Amendment No. 4 applicable in all countries: Clarification or modification of the study selection and inclusion criteria : - Selection criterion 3: Paroxysmal atrial fibrillation: sinus rhythm was to be recorded within maximum 7 days since the onset of this AF episode. - Selection criterion 4: Paroxysmal AF could be documented by an ECG within 18 months to demonstrate the existence of the disease. - Selection criterion 5: Wording for AF ablation slightly modified to allow countries to select patients according to local guideline (HRS/EHRA/ECAS, 2012; AHA/ACC/HRS, 2014). - Non-selection criterion 17: Patients who had been treated for persistent atrial fibrillation were considered as eligible under certain circumstances. A precautionary measure concerning gastrointestinal events was added.
    30 Oct 2015
    Amendment No. 5 applicable in all countries: Addition of extended clinical follow-up further to the decision (in agreement with the DIAGRAF-IKUR study Executive Committee, the Data Monitoring Committee) to prematurely discontinue the study treatment in all patients as a precautionary measure for all randomized patients who received at least one dose of study treatment (either placebo or S066913). The follow-up consists of an initial visit and a second follow-up visit 6 months later.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Sep 2015
    The Sponsor decided, in agreement with the study Data Monitoring Committee and Executive Committee, to prematurely discontinue the study treatment as a precautionary measure and to implement a clinical follow-up period with two visits separated by 6 months in all patients having taken the study treatment at least once.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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