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    Clinical Trial Results:
    Long-Term Safety Study in Patients Included in CLARINET Study With Cyanotic Congenital Heart Disease Palliated With A Systemic-To-Pulmonary Artery Shunt And For Whom The Shunt is Still in Place at One Year of Age

    Summary
    EudraCT number
    		 2008-004999-53
    Trial protocol
    		 PT   HU   ES   BE   DE   FR   IT   GB   Outside EU/EEA  
    Global end of trial date
    21 Jul 2010

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 May 2016
    First version publication date
    20 Dec 2014
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Minor correction to non-serious adverse events data (number of occurrences)

    Trial information

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    Trial identification
    Sponsor protocol code
    LTS10916
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00833703
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000049-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jul 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jul 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the safety up to 18 months of age of the extended use of Clopidogrel (SR25990C, Iscover®, Plavix®) 0.2 milligram/kilogram of body weight/day (mg/kg/day) in subjects for whom the shunt was still in place at one year of age.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of pediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort.
    Background therapy
    		 All drugs usually required in subject with systemic-to-pulmonary artery shunts were authorized for concomitant use with the study drug. The most common concomitant medications were acetylcalicylic acid, diuretic, and antibiotics.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jan 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    India: 1
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    France: 1
    Worldwide total number of subjects
    49
    EEA total number of subjects
    19
    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)
    49
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 49 subjects were enrolled between January 2009 and January 2010 in 25 sites in 15 countries (7 countries involved in CLARINET study were not selected as the delay in obtaining IRB/IEC and Health Authorities approvals would prevent recruitment and/or no subject would be recruited as the second surgery is always performed before 1 year of age).

    Pre-assignment
    Screening details
    		 Subjects from EFC5314/CLARINET study were included.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Eligible subjects received 0.2 mg/kg/day of clopidogrel or placebo without the Investigator or the subject’s parents/guardians knowing the treatment assigned. The clopidogrel and placebo were reconstituted in the same fashion and were identical in appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 0.2 mL/kg/day matching placebo solution once daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Enteral use , Oral use
    Dosage and administration details
    Placebo matching to clopidogrel 0.2 mg/kg/day.

    Arm title
    		 Clopidogrel 0.2 mg/kg/day
    Arm description
    		 0.2 mL/kg/day clopidogrel reconstituted solution at 1 mg/mL once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    SR25990
    Other name
    Iscover®, Plavix®
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Clopidogrel powder 0.2 mg/kg/day.

    Number of subjects in period 1
    		Placebo Clopidogrel 0.2 mg/kg/day
    Started
    23
    26
    Treated
    23
    26
    Completed Treatment
    22 [1]
    24 [2]
    Completed
    23
    25
    Not completed
    0
    1
         Parent(s)/guardian(s)'s request
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Number of subjects who completed the treatment are the subjects who completed the placebo treatment as per scheduled duration; however, subjects who did not complete the treatment were followed up until end of the study period/early withdrawal.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Number of subjects who completed the treatment are the subjects who completed the clopidogrel treatment as per scheduled duration; however, subjects who did not complete the treatment were followed up until end of the study period/early withdrawal.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 0.2 mL/kg/day matching placebo solution once daily.

    Reporting group title
    Clopidogrel 0.2 mg/kg/day
    Reporting group description
    		 0.2 mL/kg/day clopidogrel reconstituted solution at 1 mg/mL once daily.

    Reporting group values
    		 Placebo Clopidogrel 0.2 mg/kg/day Total
    Number of subjects
    		 23 26 49
    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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 368.1 ( 4.2 ) 368 ( 2.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 14 24
        Male
    		 13 12 25
    Shunt on Cardiopulmonary Bypass
    Units: Subjects
        Yes
    		 2 5 7
        No
    		 21 21 42
    Type of Initial Shunt Palliation
    Units: Subjects
        Modified Blalock Taussig Shunt with Norwood
    		 0 1 1
        Modified Blalock Taussig Shunt without Norwood
    		 18 20 38
        Sano procedure with Norwood
    		 0 0 0
        Sano procedure without Norwood
    		 1 1 2
        Central Shunt
    		 1 3 4
        Stent of Ductus Arteriosus
    		 3 1 4
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    		 7.9 ( 1.1 ) 8.1 ( 1.2 ) -
    Height
    Units: centimetres (cm)
        arithmetic mean (standard deviation)
    		 71.8 ( 2.8 ) 70 ( 10.4 ) -
    Age at Shunt Palliation
    Units: days
        arithmetic mean (standard deviation)
    		 25.7 ( 28.7 ) 13.7 ( 12.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 0.2 mL/kg/day matching placebo solution once daily.

    Reporting group title
    Clopidogrel 0.2 mg/kg/day
    Reporting group description
    		 0.2 mL/kg/day clopidogrel reconstituted solution at 1 mg/mL once daily.

    Primary: Number of Subjects With Bleeding Events

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    End point title
    		 Number of Subjects With Bleeding Events [1]
    End point description
    All bleeding events experienced during the study period were collected as for any Adverse Event. The 'on-treatment' period was defined as the period from inclusion in the extension study up to 28 days after treatment discontinuation, and subjects who experienced bleeding events during that period were counted. The analysis was performed on the Intent-to-treat (ITT) population that consisted of all included subjects. Subjects were analyzed in the treatment arm allocated at randomization into the CLARINET study.
    End point type
    Primary
    End point timeframe
    Up to a maximum of 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: Analysis for this end point were descriptive.
    End point values
    		 Placebo Clopidogrel 0.2 mg/kg/day
    Number of subjects analysed
    23
    26
    Units: subjects
        Any bleeding event
    0
    2
        Serious
    0
    0
        Serious with an Outcome of Death
    0
    0
        Leading to Permanent Treatment Discontinuation
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects According to Bleeding Type/Etiology

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    End point title
    		 Number of Subjects According to Bleeding Type/Etiology [2]
    End point description
    For all reported bleeding events, the type and the etiology of the bleeding event were collected. Subjects who experienced bleeding events during the 'on-treatment period' were counted by bleeding type and etiology. Analysis was performed on ITT population.
    End point type
    Primary
    End point timeframe
    Up to a maximum of 6 months
    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: Analysis for this end point were descriptive.
    End point values
    		 Placebo Clopidogrel 0.2 mg/kg/day
    Number of subjects analysed
    23
    26
    Units: Subjects
        Spontaneous
    0
    1
        Puncture (vascular access site)
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shunt Thrombosis Requiring Intervention or Deaths

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    End point title
    		 Number of Subjects With Shunt Thrombosis Requiring Intervention or Deaths
    End point description
    Outcome events, shunt thrombosis requiring intervention or death, experienced during the study period were recorded. Subjects were counted excluding the events that occured after the subject's protocol study end (occurrence of shunt thrombosis, next surgical procedure for correction of the congenital heart disease, death, or 18 months of age, whichever came first). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Up to a maximum of 6 months
    End point values
    		 Placebo Clopidogrel 0.2 mg/kg/day
    Number of subjects analysed
    23
    26
    Units: subjects
        Shunt Thrombosis Requiring Intervention
    0
    0
        Death
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (up to maximum of Month 6) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (on-treatment period is the time from the inclusion date in the study up to 28 days after the last dose of study medication).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Clopidogrel 0.2 mg/kg/day
    Reporting group description
    		 0.2 mL/kg/day clopidogrel reconstituted solution at 1 mg/mL once daily.

    Reporting group title
    Placebo
    Reporting group description
    		 0.2 mL/kg/day matching placebo solution once daily.

    Serious adverse events
    		 Clopidogrel 0.2 mg/kg/day Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 26 (23.08%)
    3 / 23 (13.04%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Cardiac disorders
    Low Cardiac Output Syndrome
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodal Arrhythmia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic Stroke
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Diaphragmatic Paralysis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Artery Stenosis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup Infectious
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Clopidogrel 0.2 mg/kg/day Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 26 (53.85%)
    6 / 23 (26.09%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 23 (4.35%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Ear Infection
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 23 (8.70%)
         occurrences all number
    2
    2
    Lower Respiratory Tract Infection
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 23 (8.70%)
         occurrences all number
    1
    2
    Pharyngitis
         subjects affected / exposed
    1 / 26 (3.85%)
    3 / 23 (13.04%)
         occurrences all number
    1
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 26 (23.08%)
    0 / 23 (0.00%)
         occurrences all number
    9
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    None reported
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