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    Clinical Trial Results:
    Efficacy assessment of systematic folinic acid and thyroid hormone treatment on the psychomotor development of young Down Syndrome children. ACTHYF

    Summary
    EudraCT number
    		 2010-021134-66
    Trial protocol
    		 FR  
    Global end of trial date
    31 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jan 2020
    First version publication date
    01 Jan 2020
    Other versions
    Summary report(s)
    		 CSR Synopis

    Trial information

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    Trial identification
    Sponsor protocol code
    IJL-AFHT-TH10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01576705
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut Jérôme Lejeune
    Sponsor organisation address
    37 rue des Volontaires, Paris, France, 75015
    Public contact
    Dr Clotilde Mircher, Institut Jérôme Lejeune, 33 156586300, clotildemircher@institutlejeune.org
    Scientific contact
    Dr Clotilde Mircher, Institut Jérôme Lejeune, 33 156586300, clotilde.mircher@institutlejeune.org
    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
    25 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluation of the following in new born infants and very young children with Down syndrome: • the efficacy of systematic treatment with L-thyroxin at controlled doses (clinically and by ultrasensitive TSH) • the efficacy of systematic folinic acid treatment at a dose of 1 mg/kg/d • any interaction between these two treatments
    Protection of trial subjects
    Patients must be available 4 hours, spread over half a day, or before and after the meal, so that they can have a period of rest between the medical consultation and the psychological evaluation. For each blood test performed, a patch of EMLA cream was proposed to avoid the pain related to the levy.
    Background therapy
    		 During the study, the Investigator or the patient’s routine treating physician could prescribe concomitant medications or supportive therapy deemed necessary
    Evidence for comparator
    		 Placebo control was used in the absence of a standard of care
    Actual start date of recruitment
    02 Apr 2012
    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
    France: 175
    Worldwide total number of subjects
    175
    EEA total number of subjects
    175
    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)
    175
    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
    		 Recruitment date : April 2nd 2012 - December 15th 2016 Centre : Institut Jérôme Lejeune, Paris -France

    Pre-assignment
    Screening details
    		 685 patients assessed for eligibility : - 82 refused participation - 196 lost to follow-up after initial contact - 232 ineligible (mostly hypothyroidism, prematurity) - 175 patients included and randomized

    Period 1
    Period 1 title
    over all trial (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
    		 Placebo
    Arm description
    		 double placebo: Thyroxin placebo+ folinic acid placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo L-thyroxin tablets (D2M) + Placebo folinic acid capsules (Therabel)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo L-thyroxin tablets (D2M): identical excipients and presentation as active product Placebo folinic acid capsules (Therabel): identical excipients and presentation as active product

    Arm title
    		 Folinic acid: FA
    Arm description
    		 folinic acid + L-thyroxin placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Folinic acid
    Investigational medicinal product code
    Other name
    Folinoral®,Therabel
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Folinic acid (Folinoral®,Therabel): 5 mg capsules, 1.0 ± 0.3 mg/kg/d, oral; commercial preparation

    Arm title
    		 L-thyroxin
    Arm description
    		 L-thyroxin+ folinic acid placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    L-thyroxin
    Investigational medicinal product code
    Other name
    Lévothyrox®, Merck
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    L-thyroxin (Lévothyrox®, Merck): 25 μg tablets, controlled dose initiated at 3.0 ± 0.2 μg/kg/d, oral; commercial preparation

    Arm title
    		 FA + L-thyroxin
    Arm description
    		 Folinic acid + L-thyroxin
    Arm type
    		 Active comparator

    Investigational medicinal product name
    folinic acid + L-thyroxin
    Investigational medicinal product code
    Other name
    Folinoral®,Therabel+ Lévothyrox®, Merck
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    L-thyroxin (Lévothyrox®, Merck): 25 μg tablets, controlled dose initiated at 3.0 ± 0.2 μg/kg/d, oral; commercial preparation Folinic acid (Folinoral®,Therabel): 5 mg capsules, 1.0 ± 0.3 mg/kg/d, oral; commercial preparation

    Number of subjects in period 1 [1]
    		Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Started
    41
    38
    37
    40
    Analyzed
    41
    38
    37
    40
    Completed
    37
    30
    34
    37
    Not completed
    4
    8
    3
    3
         Adverse event, serious fatal
    -
    -
    -
    1
         Physician decision
    1
    1
    1
    -
         Consent withdrawn by subject
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    7
    1
    -
         Protocol deviation
    3
    -
    -
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 175 is the number of randomised patients 156 is the number of The modified ITT (mITT) population excluded the 18 patients who discontinued prematurely due to presence of elevated TSH levels at baseline , as well as the patient lacking a complete informed consent, and was thus composed of 156 patients. The main analysis of the primary endpoint was performed in the mITT. Safety was analysed in the safety population. The safety population excluded the untreated patient (randomised to L-thyroxin).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 double placebo: Thyroxin placebo+ folinic acid placebo

    Reporting group title
    Folinic acid: FA
    Reporting group description
    		 folinic acid + L-thyroxin placebo

    Reporting group title
    L-thyroxin
    Reporting group description
    		 L-thyroxin+ folinic acid placebo

    Reporting group title
    FA + L-thyroxin
    Reporting group description
    		 Folinic acid + L-thyroxin

    Reporting group values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin Total
    Number of subjects
    		 41 38 37 40 156
    Age categorical
    Units: Subjects
        6-12 Months
    		 20 20 19 21 80
        12-18 Months
    		 21 18 18 19 76
    Age continuous
    Almost all baseline characteristics were very well balanced between groups in the mITT population; median age was ~12 months in all groups.
    Units: months
        arithmetic mean (standard deviation)
    		 12.7 ( 3.3 ) 12.3 ( 4.0 ) 12.2 ( 3.8 ) 12.3 ( 3.4 ) -
    Gender categorical
    There were 55.3% to 58.5% males across groups.
    Units: Subjects
        Female
    		 17 17 16 17 67
        Male
    		 24 21 21 23 89
    karyotype
    Patient with a karyotype demonstrating homogeneous, free and complete or Robertsonian translocation trisomy 21 are included. All but 2 mITT patients (98.7%) had a free karyotype.
    Units: Subjects
        karyotype free and complete
    		 40 38 37 39 154
        Karyotype Robertsonian translocation
    		 1 0 0 1 2
    cardiac abnormalities
    Isolated heart murmur yes for subjects with isolated heart murmur Isolated heart murmur no for subjects without isolated heart murmur
    Units: Subjects
        Isolated heart murmur yes
    		 1 2 3 1 7
        Isolated heart murmur no
    		 40 36 34 39 149
    cardiac abnormalities
    Atrioventicular septal defect (AVSD) YES for subjects with Atrioventicular septal defect Atrioventicular septal defect (AVSD) NO for subjects without Atrioventicular septal defect
    Units: Subjects
        Atrioventicular septal defect (AVSD) YES
    		 2 1 1 2 6
        Atrioventicular septal defect (AVSD) NO
    		 39 37 35 38 149
        Not recorded
    		 0 0 1 0 1
    cardiac abnormalities
    Ventricular septal defect YES for subjects with Ventricular septal defect Ventricular septal defect NO for subjects without Ventricular septal defect
    Units: Subjects
        Ventricular septal defect YES
    		 10 7 5 5 27
        Ventricular septal defect NO
    		 31 31 31 35 128
        Not recorded
    		 0 0 1 0 1
    cardiac abnormalities
    Atrial septal defect YES for subjects with Atrial septal defect Atrial septal defect No for subjects without Atrial septal defect
    Units: Subjects
        Atrial septal defect YES
    		 10 8 11 15 44
        Atrial septal defect No
    		 31 30 26 25 112
    cardiac abnormalities
    Patient ductus arteriosus YES for subjects with ductus arteriosus Patient ductus arteriosus NO for subjects without ductus arteriosus
    Units: Subjects
        Patient ductus arteriosus YES
    		 6 7 6 6 25
        Patient ductus arteriosus NO
    		 35 31 30 34 130
        Not recorded
    		 0 0 1 0 1
    cardiac abnormalities
    Mitral valve prolaspse (except AVSD) YES for subjects with Mitral valve prolaspse (except AVSD) Mitral valve prolaspse (except AVSD) NO for subjects withouth Mitral valve prolaspse (except AVSD)
    Units: Subjects
        Mitral valve prolaspse (except AVSD) YES
    		 0 0 0 0 0
        Mitral valve prolaspse (except AVSD) NO
    		 41 38 36 40 155
        Not recorded
    		 0 0 1 0 1
    cardiac abnormalities
    Other cardiac abnormalities YES for subjects with Other cardiac abnormalities Other cardiac abnormalities NO for subjects without Other cardiac abnormalities
    Units: Subjects
        Other cardiac abnormalities YES
    		 9 7 7 9 32
        Other cardiac abnormalities NO
    		 32 31 29 31 123
        Not recorded
    		 0 0 1 0 1
    height
    Patients had a mean height of ~71 cm
    Units: cm
        arithmetic mean (standard deviation)
    		 71.68 ( 4.36 ) 71.13 ( 4.15 ) 71.14 ( 5.03 ) 70.86 ( 3.88 ) -
    pregnancy duration
    patients with gestational age < 231 days (35 weeks of amenorrhoea = 33 weeks of gestation) are excluded
    Units: weeks of amenorrhoea
        arithmetic mean (standard deviation)
    		 37.85 ( 0.99 ) 38.29 ( 1.33 ) 38.14 ( 0.98 ) 38.03 ( 1.37 ) -
    TSH
    Exclusion criteria: Patient with hypothyroidism demonstrated by laboratory tests with TSH >7 mIU/L
    Units: mIU/L
        arithmetic mean (standard deviation)
    		 4.45 ( 1.49 ) 4.79 ( 1.23 ) 4.32 ( 1.52 ) 4.3 ( 1.7 ) -
    weight
    Units: kg
        arithmetic mean (standard deviation)
    		 8.62 ( 1.6 ) 8.52 ( 1.13 ) 8.19 ( 1.42 ) 8.3 ( 1.2 ) -
    Subject analysis sets

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All ITT patients who did not prematurely discontinue the study due to high baseline TSH levels (per exclusion criterion #8).

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All mITT patients having taken the study medication and without major protocol violations

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients with valid informed consent, regardless of whether they received study treatment

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised patients receiving at least one dose of study treatment

    Subject analysis set title
    All-randomized
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised patients regardless of whether they received study treatment

    Subject analysis sets values
    		 mITT PP ITT Safety All-randomized
    Number of subjects
    156
    138
    175
    174
    175
    Age categorical
    Units: Subjects
        6-12 Months
        12-18 Months
    Age continuous
    Almost all baseline characteristics were very well balanced between groups in the mITT population; median age was ~12 months in all groups.
    Units: months
        arithmetic mean (standard deviation)
    12.37 ( 3.58 )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    There were 55.3% to 58.5% males across groups.
    Units: Subjects
        Female
    67
        Male
    89
    karyotype
    Patient with a karyotype demonstrating homogeneous, free and complete or Robertsonian translocation trisomy 21 are included. All but 2 mITT patients (98.7%) had a free karyotype.
    Units: Subjects
        karyotype free and complete
    154
        Karyotype Robertsonian translocation
    2
    cardiac abnormalities
    Isolated heart murmur yes for subjects with isolated heart murmur Isolated heart murmur no for subjects without isolated heart murmur
    Units: Subjects
        Isolated heart murmur yes
        Isolated heart murmur no
    cardiac abnormalities
    Atrioventicular septal defect (AVSD) YES for subjects with Atrioventicular septal defect Atrioventicular septal defect (AVSD) NO for subjects without Atrioventicular septal defect
    Units: Subjects
        Atrioventicular septal defect (AVSD) YES
        Atrioventicular septal defect (AVSD) NO
        Not recorded
    cardiac abnormalities
    Ventricular septal defect YES for subjects with Ventricular septal defect Ventricular septal defect NO for subjects without Ventricular septal defect
    Units: Subjects
        Ventricular septal defect YES
        Ventricular septal defect NO
        Not recorded
    cardiac abnormalities
    Atrial septal defect YES for subjects with Atrial septal defect Atrial septal defect No for subjects without Atrial septal defect
    Units: Subjects
        Atrial septal defect YES
        Atrial septal defect No
    cardiac abnormalities
    Patient ductus arteriosus YES for subjects with ductus arteriosus Patient ductus arteriosus NO for subjects without ductus arteriosus
    Units: Subjects
        Patient ductus arteriosus YES
        Patient ductus arteriosus NO
        Not recorded
    cardiac abnormalities
    Mitral valve prolaspse (except AVSD) YES for subjects with Mitral valve prolaspse (except AVSD) Mitral valve prolaspse (except AVSD) NO for subjects withouth Mitral valve prolaspse (except AVSD)
    Units: Subjects
        Mitral valve prolaspse (except AVSD) YES
        Mitral valve prolaspse (except AVSD) NO
        Not recorded
    cardiac abnormalities
    Other cardiac abnormalities YES for subjects with Other cardiac abnormalities Other cardiac abnormalities NO for subjects without Other cardiac abnormalities
    Units: Subjects
        Other cardiac abnormalities YES
        Other cardiac abnormalities NO
        Not recorded
    height
    Patients had a mean height of ~71 cm
    Units: cm
        arithmetic mean (standard deviation)
    71.21 ( 4.33 )
    ( )
    ( )
    ( )
    ( )
    pregnancy duration
    patients with gestational age < 231 days (35 weeks of amenorrhoea = 33 weeks of gestation) are excluded
    Units: weeks of amenorrhoea
        arithmetic mean (standard deviation)
    38.07 ( 1.18 )
    ( )
    ( )
    ( )
    ( )
    TSH
    Exclusion criteria: Patient with hypothyroidism demonstrated by laboratory tests with TSH >7 mIU/L
    Units: mIU/L
        arithmetic mean (standard deviation)
    4.46 ( 1.5 )
    ( )
    ( )
    ( )
    ( )
    weight
    Units: kg
        arithmetic mean (standard deviation)
    8.42 ( 1.35 )
    ( )
    ( )
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 double placebo: Thyroxin placebo+ folinic acid placebo

    Reporting group title
    Folinic acid: FA
    Reporting group description
    		 folinic acid + L-thyroxin placebo

    Reporting group title
    L-thyroxin
    Reporting group description
    		 L-thyroxin+ folinic acid placebo

    Reporting group title
    FA + L-thyroxin
    Reporting group description
    		 Folinic acid + L-thyroxin

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All ITT patients who did not prematurely discontinue the study due to high baseline TSH levels (per exclusion criterion #8).

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All mITT patients having taken the study medication and without major protocol violations

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients with valid informed consent, regardless of whether they received study treatment

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised patients receiving at least one dose of study treatment

    Subject analysis set title
    All-randomized
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised patients regardless of whether they received study treatment

    Primary: Griffiths Mental Development Scales (GMDS)

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    End point title
    		 Griffiths Mental Development Scales (GMDS)
    End point description
    Adjusted change from baseline in Global Development Quotient (GDQ) at Visit 3 using the Griffiths Mental Development Scales (GMDS).
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    41
    38
    37
    40
    Units: Adjusted change in GMDS GDQ value
        arithmetic mean (confidence interval 95%)
    -5.1 (-7.8 to -2.4)
    -4.7 (-7.7 to -1.6)
    -3.9 (-6.9 to -0.8)
    -3.9 (-6.7 to -1.1)
    Statistical analysis title
    		 Comparison of treatment groups
    Statistical analysis description
    ANCOVA adjusted for covariates (sex, age class at randomisation, pair of neuropsychologists at Visit 1 and 3 and baseline value of GDQ)
    Comparison groups
    Folinic acid: FA v L-thyroxin v FA + L-thyroxin v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [1] - Difference to placebo, unadjusted Student p-value: - FA: p=0.3919 - L-Thyroxin: p=0.2019 -FA + L-Thyroxin: p=1878

    Secondary: Brunet-Lézine psychomotor development scale (BL-R GDQ)

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    End point title
    		 Brunet-Lézine psychomotor development scale (BL-R GDQ)
    End point description
    Change from baseline in the Brunet-Lézine Revised (BL-R) GDQ at Visit 3
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    41
    38
    35
    38
    Units: Brunet-Lézine Revised (BL-R) GDQ value
        arithmetic mean (confidence interval 95%)
    -8.9 (-11.7 to -6.1)
    -8.3 (-11.4 to -5.2)
    -8.0 (-11.1 to -4.9)
    -8.7 (-11.5 to -5.8)
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA adjusted for covariates
    Comparison groups
    Placebo v Folinic acid: FA v L-thyroxin v FA + L-thyroxin
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - Difference to placebo: unadjusted Student p-value: - FA: p=0.3575 - L-Thyroxin: p=0.2696 - FA+L-Thyroxin: p=0.4407

    Secondary: Biometric parameters : Height

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    End point title
    		 Biometric parameters : Height
    End point description
    Adjusted mean change from baseline in height
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    41
    38
    37
    40
    Units: cm
        arithmetic mean (confidence interval 95%)
    9.9 (9.4 to 10.5)
    10.0 (9.3 to 10.7)
    9.3 (8.7 to 9.9)
    9.7 (9.2 to 10.3)
    No statistical analyses for this end point

    Secondary: Biometric parameters: Head circumference

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    End point title
    		 Biometric parameters: Head circumference
    End point description
    Adjusted mean change from baseline in head circumference
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    41
    38
    37
    40
    Units: cm
        arithmetic mean (confidence interval 95%)
    2.0 (1.8 to 2.2)
    2.1 (1.9 to 2.3)
    2.1 (1.9 to 2.3)
    1.9 (1.7 to 2.1)
    No statistical analyses for this end point

    Secondary: Safety Exposure

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    End point title
    		 Safety Exposure
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Safety
    Number of subjects analysed
    174
    Units: month
    11
    No statistical analyses for this end point

    Secondary: Safety Adverse events (TEAE)

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    End point title
    		 Safety Adverse events (TEAE)
    End point description
    Almost all patients in the safety population experienced at least one TEAE (Treatment Emergent Adverse Event).
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Safety
    Number of subjects analysed
    174
    Units: count of participants
    154
    No statistical analyses for this end point

    Secondary: Safety Related TEAEs

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    End point title
    		 Safety Related TEAEs
    End point description
    Related TEAEs (Treatment Emergent Adverse Event)
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Safety
    Number of subjects analysed
    174
    Units: count of participants
    9
    No statistical analyses for this end point

    Secondary: Safety Serious TEAEs

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    End point title
    		 Safety Serious TEAEs
    End point description
    serious treatment emergent adverse events
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Safety
    Number of subjects analysed
    174
    Units: count of participants
    30
    No statistical analyses for this end point

    Secondary: Safety TEAEs leading to treatment discontinuation

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    End point title
    		 Safety TEAEs leading to treatment discontinuation
    End point description
    adverse events leading to permanent discontinuation
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Safety
    Number of subjects analysed
    174
    Units: count of participants
    7
    No statistical analyses for this end point

    Secondary: Safety Laboratory events

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    End point title
    		 Safety Laboratory events
    End point description
    Treatment emergent laboratory abnormalities
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Safety
    Number of subjects analysed
    174
    Units: participants count
    38
    No statistical analyses for this end point

    Secondary: Safety abnormal general examination

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    End point title
    		 Safety abnormal general examination
    End point description
    End point type
    Secondary
    End point timeframe
    12months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    40
    30
    35
    38
    Units: abnormal general examination count
    29
    22
    24
    27
    No statistical analyses for this end point

    Secondary: Vital signs change from baseline : weight

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    End point title
    		 Vital signs change from baseline : weight
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    40
    30
    35
    38
    Units: Kg
        arithmetic mean (standard deviation)
    2.13 ( 0.85 )
    2.07 ( 0.72 )
    2.23 ( 0.55 )
    2.21 ( 0.88 )
    No statistical analyses for this end point

    Secondary: Vital signs change from baseline : Systolic blood pressure

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    End point title
    		 Vital signs change from baseline : Systolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    40
    30
    34
    38
    Units: mmHg
        arithmetic mean (standard deviation)
    3.55 ( 13.32 )
    4.13 ( 16.60 )
    6.44 ( 13.29 )
    5.21 ( 13.94 )
    No statistical analyses for this end point

    Secondary: Vital signs change from baseline : Diastolic blood pressure

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    End point title
    		 Vital signs change from baseline : Diastolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    40
    30
    34
    38
    Units: mmHg
        arithmetic mean (standard deviation)
    4.43 ( 14.74 )
    6.17 ( 15.45 )
    8.18 ( 13.70 )
    5.63 ( 12.79 )
    No statistical analyses for this end point

    Secondary: Vital signs change from baseline : Heart rate

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    End point title
    		 Vital signs change from baseline : Heart rate
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    40
    30
    34
    38
    Units: bpm
        arithmetic mean (standard deviation)
    -9.70 ( 19.07 )
    -7.30 ( 19.11 )
    -5.82 ( 21.25 )
    0.32 ( 21.98 )
    No statistical analyses for this end point

    Secondary: Safety TEAEs leading to death

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    End point title
    		 Safety TEAEs leading to death
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Safety
    Number of subjects analysed
    174
    Units: count of participants
    1
    No statistical analyses for this end point

    Other pre-specified: Clinical global impression (CGI)

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    End point title
    		 Clinical global impression (CGI)
    End point description
    Overall evolution of CGI at Visit 3 from baseline
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin mITT
    Number of subjects analysed
    40
    30
    35
    38
    143
    Units: count of participants
        No progress
    2
    1
    0
    0
    3
        Slight progress
    27
    16
    22
    18
    83
        Marked progress
    11
    13
    12
    20
    56
        Very marked progress
    0
    0
    1
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Correlations between GMDS and BL-R GDQ

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    End point title
    		 Correlations between GMDS and BL-R GDQ
    End point description
    Correlations between GMDS and BL/R GDQ values at Visits 2 and 3 and between changes from baseline in GMDS and BL/R GDQ at Visits 2 and 3
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    40
    30
    35
    38
    Units: Correlation coefficient
        number (confidence interval 95%)
    0.94 (0.89 to 0.97)
    0.93 (0.86 to 0.97)
    0.93 (0.85 to 0.96)
    0.93 (0.90 to 0.95)
    No statistical analyses for this end point

    Post-hoc: Change from baseline in Free T4

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    End point title
    		 Change from baseline in Free T4
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    40
    29
    34
    38
    Units: pmol/L
        arithmetic mean (standard deviation)
    -0.48 ( 2.25 )
    -1.18 ( 2.09 )
    2.92 ( 3.08 )
    2.47 ( 3.76 )
    No statistical analyses for this end point

    Post-hoc: Change from baseline in TSH

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    End point title
    		 Change from baseline in TSH
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    40
    30
    35
    38
    Units: µU/mL
        arithmetic mean (standard deviation)
    0.52 ( 2.01 )
    -0.54 ( 1.98 )
    -1.96 ( 1.56 )
    -1.91 ( 2.14 )
    No statistical analyses for this end point

    Post-hoc: Change from baseline in Total Folates

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    End point title
    		 Change from baseline in Total Folates
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    14
    15
    12
    17
    Units: nmol/L
        arithmetic mean (standard deviation)
    -20.25 ( 23.39 )
    1288.98 ( 898.78 )
    -13.01 ( 19.43 )
    2569.53 ( 5318.28 )
    No statistical analyses for this end point

    Post-hoc: Change from baseline in Homocysteine

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    End point title
    		 Change from baseline in Homocysteine
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    34
    27
    31
    31
    Units: µmol/L
        arithmetic mean (standard deviation)
    -0.19 ( 1.40 )
    -0.71 ( 1.29 )
    0.14 ( 1.47 )
    -1.09 ( 2.74 )
    No statistical analyses for this end point

    Post-hoc: Change from baseline in S-Adenosyl Methionine

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    End point title
    		 Change from baseline in S-Adenosyl Methionine
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Number of subjects analysed
    34
    27
    31
    31
    Units: nmol/L
        arithmetic mean (standard deviation)
    -8.32 ( 19.81 )
    16.83 ( 26.20 )
    -12.30 ( 23.52 )
    14.63 ( 38.03 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    pneumonia viral12 months
    Adverse event reporting additional description
    Adverse event assessment was to be performed throughout the study . AEs occurring after the end of this observation period were to be reported by the investigator if he/she considered that there was a causal relationship with the study product. Standard AE definitions, monitoring and reporting were used.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 double placebo: Thyroxin placebo+ folinic acid placebo

    Reporting group title
    Folinic acid: FA
    Reporting group description
    		 folinic acid + L-thyroxin placebo

    Reporting group title
    L-thyroxin
    Reporting group description
    		 L-thyroxin+ folinic acid placebo

    Reporting group title
    FA + L-thyroxin
    Reporting group description
    		 folinic acid + L-thyroxin

    Serious adverse events
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 44 (11.36%)
    8 / 43 (18.60%)
    9 / 44 (20.45%)
    8 / 43 (18.60%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (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
    Burns second degree
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (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
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Surgical and medical procedures
    Hernia diaphragmatic repair
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (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
    Lacrimal duct procedure
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Adenoidectomy
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Infantile spasms
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         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
    Sudden death
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         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 / 1
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 43 (4.65%)
    1 / 44 (2.27%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    2 / 44 (4.55%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (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
    Choking
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         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
    INFANTILE ASTHMA
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Interstitial lung disease
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Pneumonia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         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
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (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
    Acute haemorrhagic oedema of infancy
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         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
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         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
    Pyelonephritis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Laryngitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Lung infection
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (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
    OTITIS MEDIA ACUTE
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (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
    Pharyngitis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (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
    Pneumonia viral
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    2 / 44 (4.55%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Folinic acid: FA L-thyroxin FA + L-thyroxin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 44 (100.00%)
    38 / 43 (88.37%)
    36 / 44 (81.82%)
    40 / 43 (93.02%)
    Surgical and medical procedures
    Adenoidectomy
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Middle ear prosthesis insertion
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis prophylaxis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    12 / 44 (27.27%)
    15 / 43 (34.88%)
    11 / 44 (25.00%)
    14 / 43 (32.56%)
         occurrences all number
    20
    16
    13
    30
    Crying
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    OEDEMA
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 44 (18.18%)
    4 / 43 (9.30%)
    5 / 44 (11.36%)
    4 / 43 (9.30%)
         occurrences all number
    10
    4
    8
    4
    Lung disorder
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 43 (2.33%)
    2 / 44 (4.55%)
    3 / 43 (6.98%)
         occurrences all number
    3
    2
    2
    5
    Asthma
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 43 (6.98%)
    2 / 44 (4.55%)
    1 / 43 (2.33%)
         occurrences all number
    1
    6
    2
    1
    Bronchial obstruction
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 43 (2.33%)
    2 / 44 (4.55%)
    1 / 43 (2.33%)
         occurrences all number
    5
    2
    3
    1
    ASTHMATIC CRISIS
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    0
    0
    3
    Dyspnoea
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    1
    2
    Rhinitis allergic
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Alveolitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Increased upper airway secretion
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal obstruction
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Stridor
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper airway obstruction
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    infantile asthma
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Neutrophil count abnormal
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Serum ferritin decreased
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sleep study abnormal
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Craniocerebral injury
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lip injury
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    2
    Cardiac disorders
    Mitral valve incompetence
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Pericardial effusion
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    2
    Tachycardia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Infantile spasms
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 43 (6.98%)
    2 / 44 (4.55%)
    2 / 43 (4.65%)
         occurrences all number
    1
    3
    2
    2
    Anaemia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    4 / 44 (9.09%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    4
    0
    NEUTROPHILIA
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 43 (4.65%)
    1 / 44 (2.27%)
    2 / 43 (4.65%)
         occurrences all number
    0
    2
    2
    2
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 43 (2.33%)
    1 / 44 (2.27%)
    1 / 43 (2.33%)
         occurrences all number
    1
    1
    1
    1
    LEUKOPENIA
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    3 / 44 (6.82%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Lymphopenia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    2 / 44 (4.55%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    1
    2
    Leukocytosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Monocytosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Deafness
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Hypermetropia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    3 / 44 (6.82%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    3
    1
    Astigmatism
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    2 / 43 (4.65%)
         occurrences all number
    1
    0
    1
    2
    Strabismus
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Chalazion
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Keratitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Myopia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    9 / 44 (20.45%)
    7 / 43 (16.28%)
    7 / 44 (15.91%)
    8 / 43 (18.60%)
         occurrences all number
    9
    8
    7
    9
    Diarrhoea
         subjects affected / exposed
    7 / 44 (15.91%)
    7 / 43 (16.28%)
    5 / 44 (11.36%)
    8 / 43 (18.60%)
         occurrences all number
    10
    10
    6
    8
    Constipation
         subjects affected / exposed
    5 / 44 (11.36%)
    2 / 43 (4.65%)
    7 / 44 (15.91%)
    3 / 43 (6.98%)
         occurrences all number
    7
    2
    9
    3
    Teething
         subjects affected / exposed
    4 / 44 (9.09%)
    3 / 43 (6.98%)
    4 / 44 (9.09%)
    6 / 43 (13.95%)
         occurrences all number
    4
    4
    7
    19
    Vomiting
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    2
    0
    0
    3
    Abnormal faeces
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    1 / 43 (2.33%)
         occurrences all number
    2
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    1
    0
    0
    1
    Aphthous ulcer
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Faeces hard
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    FREQUENT BOWEL MOVEMENTS
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    STOMATITIS
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 44 (9.09%)
    3 / 43 (6.98%)
    4 / 44 (9.09%)
    5 / 43 (11.63%)
         occurrences all number
    5
    3
    5
    7
    Eczema
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    2 / 44 (4.55%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Urticaria
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    2 / 44 (4.55%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Purpura
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    1
    1
    Dermatitis diaper
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    2
    Dry skin
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Petechiae
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Prurigo
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rosacea
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 44 (0.00%)
    5 / 43 (11.63%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Musculoskeletal and connective tissue disorders
    Growth retardation
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    21 / 44 (47.73%)
    20 / 43 (46.51%)
    15 / 44 (34.09%)
    16 / 43 (37.21%)
         occurrences all number
    32
    31
    30
    22
    Ear infection
         subjects affected / exposed
    19 / 44 (43.18%)
    13 / 43 (30.23%)
    14 / 44 (31.82%)
    21 / 43 (48.84%)
         occurrences all number
    25
    24
    26
    48
    Rhinitis
         subjects affected / exposed
    16 / 44 (36.36%)
    9 / 43 (20.93%)
    17 / 44 (38.64%)
    17 / 43 (39.53%)
         occurrences all number
    23
    14
    22
    25
    Bronchitis
         subjects affected / exposed
    15 / 44 (34.09%)
    8 / 43 (18.60%)
    13 / 44 (29.55%)
    17 / 43 (39.53%)
         occurrences all number
    25
    11
    23
    25
    Gastroenteritis
         subjects affected / exposed
    12 / 44 (27.27%)
    13 / 43 (30.23%)
    13 / 44 (29.55%)
    10 / 43 (23.26%)
         occurrences all number
    16
    17
    13
    13
    Conjunctivitis
         subjects affected / exposed
    14 / 44 (31.82%)
    7 / 43 (16.28%)
    12 / 44 (27.27%)
    14 / 43 (32.56%)
         occurrences all number
    18
    8
    21
    19
    Bronchiolitis
         subjects affected / exposed
    10 / 44 (22.73%)
    7 / 43 (16.28%)
    9 / 44 (20.45%)
    11 / 43 (25.58%)
         occurrences all number
    11
    12
    10
    17
    Tonsillitis
         subjects affected / exposed
    5 / 44 (11.36%)
    2 / 43 (4.65%)
    8 / 44 (18.18%)
    13 / 43 (30.23%)
         occurrences all number
    5
    2
    10
    21
    varicella
         subjects affected / exposed
    3 / 44 (6.82%)
    8 / 43 (18.60%)
    8 / 44 (18.18%)
    8 / 43 (18.60%)
         occurrences all number
    3
    9
    8
    8
    Laryngitis
         subjects affected / exposed
    2 / 44 (4.55%)
    7 / 43 (16.28%)
    7 / 44 (15.91%)
    6 / 43 (13.95%)
         occurrences all number
    2
    14
    10
    6
    Otitis media
         subjects affected / exposed
    3 / 44 (6.82%)
    3 / 43 (6.98%)
    5 / 44 (11.36%)
    5 / 43 (11.63%)
         occurrences all number
    5
    4
    5
    5
    HAND-FOOT-AND-MOUTH DISEASE
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 43 (4.65%)
    3 / 44 (6.82%)
    4 / 43 (9.30%)
         occurrences all number
    1
    2
    3
    4
    Influenza
         subjects affected / exposed
    4 / 44 (9.09%)
    3 / 43 (6.98%)
    0 / 44 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    5
    4
    0
    3
    Viral infection
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 43 (4.65%)
    2 / 44 (4.55%)
    5 / 43 (11.63%)
         occurrences all number
    1
    2
    2
    5
    Pharyngitis
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 43 (0.00%)
    3 / 44 (6.82%)
    1 / 43 (2.33%)
         occurrences all number
    4
    0
    3
    1
    Roseola
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 43 (4.65%)
    1 / 44 (2.27%)
    3 / 43 (6.98%)
         occurrences all number
    1
    2
    1
    3
    Oral candidiasis
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 43 (2.33%)
    2 / 44 (4.55%)
    1 / 43 (2.33%)
         occurrences all number
    2
    2
    2
    1
    SCARLET FEVER
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 43 (2.33%)
    2 / 44 (4.55%)
    0 / 43 (0.00%)
         occurrences all number
    2
    1
    2
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Oral fungal infection
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    1 / 43 (2.33%)
         occurrences all number
    3
    0
    1
    1
    Oral herpes
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    1 / 43 (2.33%)
         occurrences all number
    2
    0
    1
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    2
    1
    FUNGAL INFECTION
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    1
    1
    0
    1
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tracheitis
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 43 (4.65%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    2
    0
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    1
    4
    Paronychia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Abscess oral
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Candida nappy rash
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Coxsackie viral infection
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    CYTOMEGALOVIRUS INFECTION
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    ENTEROBIASIS
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Erythema infectiosum
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Hordeolum
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infection
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Purulent discharge
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Rhinotracheitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tonsillitis bacterial
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    TRACHEOBRONCHITIS
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Viral rash
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Viral tonsillitis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    3 / 44 (6.82%)
    6 / 43 (13.95%)
    6 / 44 (13.64%)
    7 / 43 (16.28%)
         occurrences all number
    3
    7
    6
    7
    Decreased appetite
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    1
    1
    Weight gain poor
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    1
    1
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2012
    Protocol version #11 (Amendment #1) Modification of inclusion criteria, addition of withdrawal criterion
    09 Oct 2012
    Protocol version #12 (Amendment #2) Protocol version #11 (13 July 2012) renumbered version # 12 after approval byEC/HA 09 October 2012 (no change to protocol)
    26 Nov 2013
    Protocol version #13 (Amendment #3) Modification of inclusion/exclusion criteria, removal of endpoint, clarification of sample collection, stopping rule, and follow-up
    06 Mar 2014
    Protocol version #13 (Amendment #4) Modified list of investigators only (no change to protocol)
    13 Oct 2014
    Protocol version #15 (Amendment #5) Modification of inclusion criterion, clarification of SAE reporting
    09 Jun 2015
    Protocol version #15 (Amendment #6) Modified list of investigators only (no change to protocol)
    12 Jun 2015
    Protocol version #16 (Amendment #7) Change in sample size and addition of a second interim analysis
    13 Nov 2015
    Protocol version #17 (Amendment #8) Change in sample size and removal of both interim analyses; modification of statistical methodology
    20 Jul 2017
    Protocol version #19 (Amendment #9) Specification of genomic analyses, addition of creatine dosing, modified list of investigators

    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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    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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