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    Clinical Trial Results:
    RAINBOW extension study: an extension study to evaluate the long-term efficacy and safety of RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity

    Summary
    EudraCT number
    		 2014-004048-36
    Trial protocol
    		 HU   EE   GB   SK   IT   BE   LT   CZ   DE   AT   SE   GR   DK   FR   HR   PL  
    Global end of trial date
    21 Apr 2022

    Results information
    Results version number
    		 v3(current)
    This version publication date
    03 Feb 2023
    First version publication date
    05 Nov 2022
    Other versions
    		 v1 , v2
    Version creation reason
    • New data added to full data set
    Alignment with CT.gov form due to major QA comment received

    Trial information

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    Trial identification
    Sponsor protocol code
    CRFB002H2301E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02640664
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Apr 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the visual function of patients, by assessing the visual acuity (VA) in the better-seeing eye at the patients’ 5th birthday.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Egypt: 1
    Country: Number of subjects enrolled
    India: 23
    Country: Number of subjects enrolled
    Japan: 25
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Saudi Arabia: 1
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    United States: 15
    Country: Number of subjects enrolled
    Czechia: 9
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Croatia: 5
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Russian Federation: 18
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    United Kingdom: 4
    Worldwide total number of subjects
    180
    EEA total number of subjects
    74
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    3
    Infants and toddlers (28 days-23 months)
    177
    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
    		 Study was carried out in Austria (2), Belgium (2), Croatia (1), Czech Republic (3), Denmark (1), Egypt (1), Estonia (1), France (2), Germany (1), Greece (3), Hungary (2), India (6), Italy (4), Japan (16), Lithuania (1), Malaysia (2), Romania (3), Russian Federation (5), Saudi Arabia (1), Slovakia (1), Taiwan (2), Turkey (3), UK (2), US (9)

    Pre-assignment
    Screening details
    		 During Epoch 1 (starting at the baseline visit for the extension study up to 40 weeks from the baseline visit in the core study) participants continued to receive same treatment as in the core study. During Epoch 2 (starting at the end of Epoch 1 up to participant's 5th birthday) participants no longer received treatment.

    Period 1
    Period 1 title
    Core study: Epoch 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study where the VA assessment at the child's 5th birthday visit was performed by an assessor who was masked to study treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ranibizumab 0.2 mg
    Arm description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    RFB002
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Arm title
    		 Ranibizumab 0.1 mg
    Arm description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    RFB002
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Arm title
    		 Laser therapy
    Arm description
    		 Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed
    Arm type
    		 laser ablation therapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Started
    61
    65
    54
    Completed
    60
    65
    53
    Not completed
    1
    0
    1
         Adverse event, serious fatal
    -
    -
    1
         Withdrawal of informed consent
    1
    -
    -
    Period 2
    Period 2 title
    Extension study: Epoch 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study where the VA assessment at the child's 5th birthday visit was performed by an assessor who was masked to study treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ranibizumab 0.2 mg
    Arm description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    RFB002
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Arm title
    		 Ranibizumab 0.1 mg
    Arm description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    RFB002
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Arm title
    		 Laser therapy
    Arm description
    		 Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed
    Arm type
    		 laser ablation therapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Started
    60
    65
    53
    Completed
    54
    55
    47
    Not completed
    6
    10
    6
         Adverse event, serious fatal
    -
    -
    1
         Withdrawal of informed consent
    3
    4
    2
         Lost to follow-up
    3
    4
    1
         Subject/guardian decision
    -
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ranibizumab 0.2 mg
    Reporting group description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Reporting group title
    Ranibizumab 0.1 mg
    Reporting group description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Reporting group title
    Laser therapy
    Reporting group description
    		 Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed

    Reporting group values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy Total
    Number of subjects
    		 61 65 54 180
    Age categorical
    Age at extension baseline visit
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 61 65 54 180
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Age at extension baseline visit
    Units: weeks
        arithmetic mean (standard deviation)
    		 38.88 ( 7.316 ) 40.16 ( 9.836 ) 37.48 ( 8.745 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 32 35 27 94
        Male
    		 29 30 27 86
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 38 40 32 110
        Black
    		 0 4 2 6
        Asian
    		 22 18 18 58
        Native American
    		 0 0 0 0
        Pacific Islander
    		 0 0 0 0
        Unknown
    		 0 0 0 0
        Other
    		 1 3 2 6

    End points

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    End points reporting groups
    Reporting group title
    Ranibizumab 0.2 mg
    Reporting group description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Reporting group title
    Ranibizumab 0.1 mg
    Reporting group description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Reporting group title
    Laser therapy
    Reporting group description
    		 Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed
    Reporting group title
    Ranibizumab 0.2 mg
    Reporting group description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Reporting group title
    Ranibizumab 0.1 mg
    Reporting group description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Reporting group title
    Laser therapy
    Reporting group description
    		 Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed

    Primary: Visual acuity (VA) of the better-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms

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    End point title
    		 Visual acuity (VA) of the better-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms
    End point description
    The VA assessment at the child’s 5th birthday visit was performed using Early Treatment Diabetic Retinopathy Study (ETDRS) methodology. VA measurements were taken in a sitting position at an initial test distance of 3 meters using Lea Symbols charts. Scores represented the number of optotypes (Lea symbols) the participant identified and ranged from 0 to 100, with higher scores indicating better visual acuity. VA was tested in each eye, using the child’s current refractive index. The better-seeing eye was defined as the eye with the higher ETDRS score at the 5th birthday visit. If both eyes had the same ETDRS score, then the right eye was assigned as the better-seeing eye.
    End point type
    Primary
    End point timeframe
    at the participant’s fifth birthday visit (maximum 5 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    45
    43
    36
    Units: Score
        least squares mean (standard error)
    66.8 ( 1.95 )
    64.6 ( 2.00 )
    62.1 ( 2.18 )
    Statistical analysis title
    		 Ranibizumab 0.2 mg vs Laser
    Comparison groups
    Ranibizumab 0.2 mg v Laser therapy
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 10.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.93
    Statistical analysis title
    		 Ranibizumab 0.2 mg vs Ranibizumab 0.1 mg
    Comparison groups
    Ranibizumab 0.2 mg v Ranibizumab 0.1 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 7.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.79
    Statistical analysis title
    		 Ranibizumab 0.1 mg vs Laser
    Comparison groups
    Ranibizumab 0.1 mg v Laser therapy
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 8.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.96

    Secondary: Number of participants with ocular adverse events (AEs) regardless of study treatment or procedure relationship by preferred term

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    End point title
    		 Number of participants with ocular adverse events (AEs) regardless of study treatment or procedure relationship by preferred term
    End point description
    Number of participants with ocular AEs starting during the core study and ongoing at extension baseline, or starting on/after extension baseline were reported.
    End point type
    Secondary
    End point timeframe
    throughout the study, approximately 5 years
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    61
    65
    54
    Units: Participants
    19
    26
    22
    No statistical analyses for this end point

    Secondary: Number of participants with non-ocular adverse events regardless of study treatment or procedure relationship (greater than or equal to 3% in any arm) by preferred term

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    End point title
    		 Number of participants with non-ocular adverse events regardless of study treatment or procedure relationship (greater than or equal to 3% in any arm) by preferred term
    End point description
    Number of participants with non-ocular adverse events (AEs) regardless of study treatment or procedure relationship (greater than or equal to 3% in any arm) by preferred term were reported.
    End point type
    Secondary
    End point timeframe
    throughout the study, approximately 5 years
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    61
    65
    54
    Units: Participants
    46
    53
    46
    No statistical analyses for this end point

    Secondary: Visual acuity (VA) of the worse-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms

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    End point title
    		 Visual acuity (VA) of the worse-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms
    End point description
    The VA assessment at the child’s 5th birthday visit was performed using Early Treatment Diabetic Retinopathy Study (ETDRS) methodology. VA measurements were taken in a sitting position at an initial test distance of 3 meters using Lea Symbols charts. Scores represented the number of optotypes (Lea symbols) the participant identified and ranged from 0 to 100, with higher scores indicating better visual acuity. VA was tested in each eye, using the child’s current refractive index. The worse-seeing eye was the eye with a lower ETDRS score at the 5th birthday visit. If both eyes had the same ETDRS score, then the left eye was assigned as the worse-seeing eye.
    End point type
    Secondary
    End point timeframe
    at the participant’s fifth birthday visit (maximum 5 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    45
    42
    36
    Units: Score
        least squares mean (standard error)
    60.2 ( 2.95 )
    53.8 ( 3.05 )
    52.2 ( 3.30 )
    Statistical analysis title
    		 Ranibizumab 0.2 mg vs Laser
    Comparison groups
    Ranibizumab 0.2 mg v Laser therapy
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 16.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.42
    Statistical analysis title
    		 Ranibizumab 0.1 mg vs Laser
    Comparison groups
    Ranibizumab 0.1 mg v Laser therapy
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 10.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.49
    Statistical analysis title
    		 Ranibizumab 0.2 mg vs Ranibizumab 0.1 mg
    Comparison groups
    Ranibizumab 0.2 mg v Ranibizumab 0.1 mg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 14.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.24

    Secondary: Number of participants with absence of active Retinopathy of Prematurity (ROP) at 40 weeks post core baseline visit

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    End point title
    		 Number of participants with absence of active Retinopathy of Prematurity (ROP) at 40 weeks post core baseline visit
    End point description
    The absence of active ROP in both eyes is defined by the absence of all of the following features: (1) Vessel dilatation of plus disease in at least 2 quardrants (some persisting tortuosity is allowed), (2) Extra-retina vessels extending from the retina into the vitreous and judged to be a sign of active ROP disease.
    End point type
    Secondary
    End point timeframe
    at 40 weeks post core baseline visit
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    55
    58
    46
    Units: Participants
        Absence of active ROP
    55
    58
    46
    No statistical analyses for this end point

    Secondary: Number of participants with absence of active Retinopathy of Prematurity (ROP) at 52 weeks post core baseline visit

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    End point title
    		 Number of participants with absence of active Retinopathy of Prematurity (ROP) at 52 weeks post core baseline visit
    End point description
    The absence of active ROP in both eyes is defined by the absence of all of the following features: (1) Vessel dilatation of plus disease in at least 2 quardrants (some persisting tortuosity is allowed), (2) Extra-retina vessels extending from the retina into the vitreous and judged to be a sign of active ROP disease.
    End point type
    Secondary
    End point timeframe
    at 52 weeks post core baseline visit
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    58
    63
    50
    Units: Participants
    58
    63
    49
    No statistical analyses for this end point

    Secondary: Number of participants with absence of all ocular structural abnormalities at or before 40 weeks post baseline visit

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    End point title
    		 Number of participants with absence of all ocular structural abnormalities at or before 40 weeks post baseline visit
    End point description
    The absence of ocular structural abnormalities is defined by the absence of all of the following fundus features in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula
    End point type
    Secondary
    End point timeframe
    at or before 40 weeks post baseline visit
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    60
    65
    53
    Units: Participants
    59
    61
    47
    No statistical analyses for this end point

    Secondary: Number of participants with absence of all ocular structural abnormalities at or before the participant’s fifth birthday visit

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    End point title
    		 Number of participants with absence of all ocular structural abnormalities at or before the participant’s fifth birthday visit
    End point description
    The absence of ocular structural abnormalities is defined by the absence of all of the following fundus features in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula
    End point type
    Secondary
    End point timeframe
    at or before the participant’s fifth birthday visit (up to maximum 5 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    60
    65
    53
    Units: Participants
    59
    61
    47
    No statistical analyses for this end point

    Secondary: Number of participants with absence of individual ocular structural abnormalities at or before 40 weeks post baseline visit

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    End point title
    		 Number of participants with absence of individual ocular structural abnormalities at or before 40 weeks post baseline visit
    End point description
    The absence of ocular structural abnormalities is defined by the absence of all of the following fundus features in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula
    End point type
    Secondary
    End point timeframe
    at or before 40 weeks post baseline visit
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    60
    65
    53
    Units: Participants
        Absence of substantial temporal retinal vessel
    59
    63
    49
        Absence of Retrolental membrane
    60
    65
    53
        Absence of posterior retinal fold
    59
    65
    51
        Absence of retinal detachment
    60
    63
    51
        Abs of retinal detachment not involving the macula
    60
    62
    50
        Absence of pre-retinal fibrosis
    58
    60
    49
    No statistical analyses for this end point

    Secondary: Number of participants with absence of individual ocular structural abnormalities at or before the participant’s fifth birthday visit

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    End point title
    		 Number of participants with absence of individual ocular structural abnormalities at or before the participant’s fifth birthday visit
    End point description
    The absence of ocular structural abnormalities is defined by the absence of all of the following fundus features in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula
    End point type
    Secondary
    End point timeframe
    at or before the participant’s fifth birthday visit (up to maximum 5 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    60
    65
    53
    Units: Participants
        Absence of temporal retinal vessel dragging
    59
    63
    49
        Absence of Retrolental membrane
    60
    65
    52
        Absence of posterior retinal fold
    59
    65
    51
        Absence of retinal detachment
    60
    63
    50
        Abs of retinal detachment not involving macula
    60
    62
    50
        Absence of pre-retinal fibrosis
    58
    59
    48
        Absence of optic disc pallor
    60
    65
    52
        Absence of optic disc swelling
    60
    65
    53
        Absence of pigmentary disturbance in the macula
    60
    64
    52
        Absence of atrophic changes in macula
    60
    65
    51
    No statistical analyses for this end point

    Secondary: Number of participants with absence of all ocular structural abnormalities at or before participant’s 2 years corrected age visit

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    End point title
    		 Number of participants with absence of all ocular structural abnormalities at or before participant’s 2 years corrected age visit
    End point description
    The absence of ocular structural abnormalities is defined by the absence of all of the following fundus features in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula
    End point type
    Secondary
    End point timeframe
    at or before participant’s 2 years corrected age visit (up to 2 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    60
    65
    53
    Units: Participants
    59
    61
    47
    No statistical analyses for this end point

    Secondary: Number of participants with absence of individual ocular structural abnormalities at or before participant’s 2 years corrected age visit

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    End point title
    		 Number of participants with absence of individual ocular structural abnormalities at or before participant’s 2 years corrected age visit
    End point description
    The absence of ocular structural abnormalities is defined by the absence of all of the following fundus features in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula
    End point type
    Secondary
    End point timeframe
    at or before participant’s 2 years corrected age visit (up to 2 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    60
    65
    53
    Units: Participants
        Abs of temporal retinal vessel dragging
    59
    63
    49
        Absence of Retrolental membrane
    60
    65
    52
        Absence of posterior retinal fold
    59
    65
    51
        Abs of retinal detachment involving the macula
    60
    63
    50
        Abs of retinal detachment not involving the macula
    60
    62
    50
        Absence of pre-retinal fibrosis
    58
    59
    48
        Absence of optic disc pallor
    60
    65
    53
        Absence of optic disc swelling
    60
    65
    53
        Absence of pigmentary disturbance in the macula
    60
    64
    52
        Absence of atrophic changes in macula
    60
    65
    52
    No statistical analyses for this end point

    Secondary: Number of participants with recurrence of ROP up to 40 weeks post baseline visit in the core study

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    End point title
    		 Number of participants with recurrence of ROP up to 40 weeks post baseline visit in the core study
    End point description
    Recurrence of ROP was defined as ROP receiving any post-baseline intervention after the 1st study treatment in the core study. In the ranibizumab arms, post-baseline interventions were ranibizumab retreatment or switch to laser. In the laser arm, post-baseline interventions were supplementary laser treatments after 11 days post-baseline, or switch to ranibizumab; supplementary laser treatment within 11 days post-baseline was not counted as recurrence.
    End point type
    Secondary
    End point timeframe
    up to 40 weeks post baseline visit in the core study
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    61
    65
    54
    Units: Participants
    19
    22
    11
    No statistical analyses for this end point

    Secondary: Number of participants with recurrence of ROP up to 52 weeks post baseline visit in the core study

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    End point title
    		 Number of participants with recurrence of ROP up to 52 weeks post baseline visit in the core study
    End point description
    Recurrence of ROP was defined as ROP receiving any post-baseline intervention after the 1st study treatment in the core study. In the ranibizumab arms, post-baseline interventions were ranibizumab retreatment or switch to laser. In the laser arm, post-baseline interventions were supplementary laser treatments after 11 days post-baseline, or switch to ranibizumab; supplementary laser treatment within 11 days post-baseline was not counted as recurrence. Beyond Week 40, participants did not receive any study intervention and no new data was collected after 40 weeks post core baseline visit.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks post baseline visit in the core study
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    61
    65
    54
    Units: Participants
    19
    22
    11
    No statistical analyses for this end point

    Secondary: Number of ranibizumab injections received per participant over the whole safety observation period

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    End point title
    		 Number of ranibizumab injections received per participant over the whole safety observation period
    End point description
    Number of ranibizumab injections received in the treatment of participants with ROP up to and including 40 weeks post baseline visit in the core study were reported.
    End point type
    Secondary
    End point timeframe
    up to and including 40 weeks post baseline visit in the core study
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    61
    65
    11
    Units: Number of injections
        arithmetic mean (standard deviation)
    2.5 ( 0.96 )
    2.5 ( 1.06 )
    2.4 ( 0.92 )
    No statistical analyses for this end point

    Secondary: Refraction status: Summary of participants at participant’s 2 years corrected age

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    End point title
    		 Refraction status: Summary of participants at participant’s 2 years corrected age
    End point description
    Summary of participants was reported to evaluate the refraction in each eye at the participant’s 2 years corrected age
    End point type
    Secondary
    End point timeframe
    at participant’s 2 years corrected age (maximum 2 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    57
    54
    47
    Units: diopters
    arithmetic mean (standard deviation)
        Best eye
    -0.697 ( 2.7032 )
    -0.713 ( 2.6100 )
    -1.793 ( 4.1570 )
        Worst eye
    -0.825 ( 2.6575 )
    -0.829 ( 2.8346 )
    -1.516 ( 3.5652 )
    No statistical analyses for this end point

    Secondary: Refraction status: Summary of participants at the participant’s fifth birthday visit

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    End point title
    		 Refraction status: Summary of participants at the participant’s fifth birthday visit
    End point description
    Summary of participants was reported to evaluate the refraction in each eye at the participant’s fifth birthday visit
    End point type
    Secondary
    End point timeframe
    at the participant’s fifth birthday visit (maximum 5 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    52
    55
    45
    Units: diopters
    arithmetic mean (standard deviation)
        Best eye
    -0.601 ( 2.8107 )
    -0.859 ( 2.7406 )
    -1.883 ( 4.4970 )
        Worst eye
    -0.904 ( 2.8501 )
    -1.074 ( 3.0405 )
    -1.706 ( 3.5740 )
    No statistical analyses for this end point

    Secondary: Change from baseline in weight at the participant’s 2 years’ corrected age

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    End point title
    		 Change from baseline in weight at the participant’s 2 years’ corrected age
    End point description
    Subject´s weight was reported to evaluate the physical development.
    End point type
    Secondary
    End point timeframe
    Baseline of the core study and at the subject’s 2 years’ corrected age (maximum 2 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    56
    58
    46
    Units: grams
    arithmetic mean (standard deviation)
        Year 2
    8695.9 ( 1406.58 )
    8461.7 ( 1375.95 )
    8840.6 ( 1643.80 )
    No statistical analyses for this end point

    Secondary: Change from baseline in weight at the participant’s fifth birthday

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    End point title
    		 Change from baseline in weight at the participant’s fifth birthday
    End point description
    Subject´s weight was reported to evaluate the physical development.
    End point type
    Secondary
    End point timeframe
    Baseline of the core study and at the subjects’ fifth birthday (maximum 5 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    52
    54
    45
    Units: grams
        arithmetic mean (standard deviation)
    14611.9 ( 3018.65 )
    14324.7 ( 2616.96 )
    14689.4 ( 3300.05 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Head Circumference

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    End point title
    		 Change from baseline in Head Circumference
    End point description
    Subject´s head circumference was reported to evaluate the physical development.
    End point type
    Secondary
    End point timeframe
    Baseline of the core study and at the subject’s 2 years’ corrected age (maximum 2 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    55
    56
    44
    Units: cm
        arithmetic mean (standard deviation)
    16.5 ( 2.60 )
    16.2 ( 2.78 )
    17.2 ( 2.81 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Sitting Diastolic Blood Pressure

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    End point title
    		 Change from baseline in Sitting Diastolic Blood Pressure
    End point description
    Subject´s Sitting Diastolic Blood Pressure was reported to evaluate the physical development.
    End point type
    Secondary
    End point timeframe
    Baseline of the core study and at the subject’s 2 years’ corrected age (maximum 2 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    38
    33
    31
    Units: mmHg
        arithmetic mean (standard deviation)
    16.7 ( 14.92 )
    13.6 ( 14.10 )
    16.5 ( 12.14 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Sitting Systolic Blood Pressure

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    End point title
    		 Change from baseline in Sitting Systolic Blood Pressure
    End point description
    Subject´s Sitting Systolic Blood Pressure was reported to evaluate the physical development.
    End point type
    Secondary
    End point timeframe
    Baseline of the core study and at the subject’s 2 years’ corrected age (maximum 2 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    38
    32
    31
    Units: mmHg
        arithmetic mean (standard deviation)
    20.6 ( 16.13 )
    16.2 ( 15.95 )
    17.6 ( 12.75 )
    No statistical analyses for this end point

    Secondary: Number of participants with the summary of respiratory function status

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    End point title
    		 Number of participants with the summary of respiratory function status
    End point description
    Number of participants with respiratory function status was reported
    End point type
    Secondary
    End point timeframe
    at the participants’ fifth birthday visit (maximum 5 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    61
    65
    54
    Units: Participants
        participants with Wheezing/whistling status
    6
    4
    2
        participants with attacks of wheezing
    47
    50
    45
        participants with frequency of sleep disturbance
    47
    52
    47
        participants with wheezing limiting speech ability
    1
    0
    0
        participants with dry cough status at night
    5
    2
    1
        participants with presence of smoker at home
    15
    8
    4
    No statistical analyses for this end point

    Secondary: Number of participants with hearing impairment of any type

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    End point title
    		 Number of participants with hearing impairment of any type
    End point description
    Number of participants with hearing function status was reported
    End point type
    Secondary
    End point timeframe
    at the participants’ fifth birthday visit (maximum 5 years and 4 months post core baseline visit)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    61
    65
    54
    Units: Participants
        Participants with hearing impairment of any type
    2
    2
    4
    No statistical analyses for this end point

    Secondary: Duration of hospitalization

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    End point title
    		 Duration of hospitalization
    End point description
    Duration of hospitalization (from birth to first hospital discharge home) was reported to evaluate the health status of the subject
    End point type
    Secondary
    End point timeframe
    From baseline of the core study up to 5 years and 4 months post core baseline visit
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    61
    65
    54
    Units: days
        arithmetic mean (standard deviation)
    111.1 ( 62.27 )
    116.2 ( 78.10 )
    95.7 ( 57.07 )
    No statistical analyses for this end point

    Secondary: Weight at the time of first hospital discharge

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    End point title
    		 Weight at the time of first hospital discharge
    End point description
    Weight (gram) at the time of first hospital discharge was reported to evaluate the health status of the subject
    End point type
    Secondary
    End point timeframe
    From baseline of the core study up to 5 years and 4 months post core baseline visit
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    56
    62
    51
    Units: gram
        arithmetic mean (standard deviation)
    2910.9 ( 1359.34 )
    2966.5 ( 1198.60 )
    2658.7 ( 926.92 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    throughout the study, up to approximately 5 years
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Ranibizumab 0.2 mg
    Reporting group description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Reporting group title
    Laser
    Reporting group description
    		 Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed

    Reporting group title
    Total
    Reporting group description
    		 Total of all the participants

    Reporting group title
    Ranibizumab 0.1 mg
    Reporting group description
    		 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

    Serious adverse events
    		 Ranibizumab 0.2 mg Laser Total Ranibizumab 0.1 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 61 (34.43%)
    26 / 54 (48.15%)
    74 / 180 (41.11%)
    27 / 65 (41.54%)
         number of deaths (all causes)
    0
    2
    2
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Perinatal brain damage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Developmental delay
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 54 (3.70%)
    6 / 180 (3.33%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 54 (3.70%)
    6 / 180 (3.33%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Bronchopulmonary dysplasia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Increased bronchial secretion
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngospasm
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal discharge discolouration
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Pulmonary hypertension
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary vein stenosis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    2 / 180 (1.11%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychomotor retardation
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Endotracheal intubation complication
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foreign body in respiratory tract
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Periorbital haematoma
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cerebral palsy
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coarctation of the aorta
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cryptorchism
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Cognitive disorder
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 54 (0.00%)
    5 / 180 (2.78%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 54 (1.85%)
    2 / 180 (1.11%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Nystagmus
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periventricular leukomalacia
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorder
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinopathy of prematurity
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    2 / 180 (1.11%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acetonaemic vomiting
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 54 (1.85%)
    4 / 180 (2.22%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Flatulence
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising colitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 54 (3.70%)
    6 / 180 (3.33%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Portal hypertension
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Rash
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticarial vasculitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteopenia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial food poisoning
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 54 (0.00%)
    7 / 180 (3.89%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 61 (4.92%)
    5 / 54 (9.26%)
    11 / 180 (6.11%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 12
    0 / 18
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Ear infection
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 54 (1.85%)
    2 / 180 (1.11%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 54 (3.70%)
    3 / 180 (1.67%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    2 / 180 (1.11%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Herpangina
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Influenza
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leptospirosis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Otitis media acute
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 54 (1.85%)
    2 / 180 (1.11%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae viral bronchitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Periorbital cellulitis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 54 (1.85%)
    4 / 180 (2.22%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 61 (3.28%)
    4 / 54 (7.41%)
    10 / 180 (5.56%)
    4 / 65 (6.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 15
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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 / 61 (1.64%)
    2 / 54 (3.70%)
    4 / 180 (2.22%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    2 / 180 (1.11%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 54 (1.85%)
    2 / 180 (1.11%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 54 (1.85%)
    3 / 180 (1.67%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    1 / 180 (0.56%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral tonsillitis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Dehydration
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 54 (1.85%)
    4 / 180 (2.22%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperphosphatasaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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
    Hypophagia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    1 / 180 (0.56%)
    0 / 65 (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: 4%
    Non-serious adverse events
    		 Ranibizumab 0.2 mg Laser Total Ranibizumab 0.1 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 61 (67.21%)
    40 / 54 (74.07%)
    127 / 180 (70.56%)
    46 / 65 (70.77%)
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    3 / 61 (4.92%)
    3 / 54 (5.56%)
    8 / 180 (4.44%)
    2 / 65 (3.08%)
         occurrences all number
    3
    4
    10
    3
    Nystagmus
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 54 (1.85%)
    5 / 180 (2.78%)
    3 / 65 (4.62%)
         occurrences all number
    1
    1
    6
    4
    Seizure
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 54 (3.70%)
    5 / 180 (2.78%)
    0 / 65 (0.00%)
         occurrences all number
    4
    2
    6
    0
    General disorders and administration site conditions
    Developmental delay
         subjects affected / exposed
    5 / 61 (8.20%)
    3 / 54 (5.56%)
    9 / 180 (5.00%)
    1 / 65 (1.54%)
         occurrences all number
    5
    3
    9
    1
    Pyrexia
         subjects affected / exposed
    6 / 61 (9.84%)
    10 / 54 (18.52%)
    27 / 180 (15.00%)
    11 / 65 (16.92%)
         occurrences all number
    6
    23
    59
    30
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 54 (1.85%)
    6 / 180 (3.33%)
    2 / 65 (3.08%)
         occurrences all number
    3
    1
    6
    2
    Eye disorders
    Astigmatism
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 54 (3.70%)
    7 / 180 (3.89%)
    2 / 65 (3.08%)
         occurrences all number
    3
    2
    7
    2
    Myopia
         subjects affected / exposed
    6 / 61 (9.84%)
    5 / 54 (9.26%)
    14 / 180 (7.78%)
    3 / 65 (4.62%)
         occurrences all number
    6
    6
    15
    3
    Strabismus
         subjects affected / exposed
    10 / 61 (16.39%)
    12 / 54 (22.22%)
    34 / 180 (18.89%)
    12 / 65 (18.46%)
         occurrences all number
    11
    12
    38
    15
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 61 (6.56%)
    2 / 54 (3.70%)
    14 / 180 (7.78%)
    8 / 65 (12.31%)
         occurrences all number
    4
    2
    17
    11
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 61 (6.56%)
    5 / 54 (9.26%)
    13 / 180 (7.22%)
    4 / 65 (6.15%)
         occurrences all number
    4
    5
    13
    4
    Diarrhoea
         subjects affected / exposed
    3 / 61 (4.92%)
    5 / 54 (9.26%)
    13 / 180 (7.22%)
    5 / 65 (7.69%)
         occurrences all number
    4
    6
    17
    7
    Vomiting
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 54 (3.70%)
    5 / 180 (2.78%)
    3 / 65 (4.62%)
         occurrences all number
    0
    2
    13
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 61 (8.20%)
    3 / 54 (5.56%)
    14 / 180 (7.78%)
    6 / 65 (9.23%)
         occurrences all number
    7
    6
    25
    12
    Bronchopulmonary dysplasia
         subjects affected / exposed
    2 / 61 (3.28%)
    4 / 54 (7.41%)
    9 / 180 (5.00%)
    3 / 65 (4.62%)
         occurrences all number
    2
    5
    10
    3
    Dyspnoea
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 54 (0.00%)
    4 / 180 (2.22%)
    3 / 65 (4.62%)
         occurrences all number
    1
    0
    10
    9
    Rhinorrhoea
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 54 (1.85%)
    6 / 180 (3.33%)
    3 / 65 (4.62%)
         occurrences all number
    2
    2
    10
    6
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 54 (5.56%)
    5 / 180 (2.78%)
    0 / 65 (0.00%)
         occurrences all number
    2
    3
    5
    0
    Erythema
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    3 / 180 (1.67%)
    3 / 65 (4.62%)
         occurrences all number
    0
    0
    3
    3
    Rash
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    3 / 180 (1.67%)
    3 / 65 (4.62%)
         occurrences all number
    0
    0
    3
    3
    Psychiatric disorders
    Autism spectrum disorder
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 54 (1.85%)
    5 / 180 (2.78%)
    1 / 65 (1.54%)
         occurrences all number
    3
    1
    5
    1
    Musculoskeletal and connective tissue disorders
    Rickets
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 54 (5.56%)
    3 / 180 (1.67%)
    0 / 65 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 54 (0.00%)
    5 / 180 (2.78%)
    3 / 65 (4.62%)
         occurrences all number
    4
    0
    7
    3
    COVID-19
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 54 (5.56%)
    5 / 180 (2.78%)
    1 / 65 (1.54%)
         occurrences all number
    1
    3
    6
    2
    Bronchitis
         subjects affected / exposed
    4 / 61 (6.56%)
    6 / 54 (11.11%)
    14 / 180 (7.78%)
    4 / 65 (6.15%)
         occurrences all number
    11
    9
    24
    4
    Conjunctivitis
         subjects affected / exposed
    2 / 61 (3.28%)
    4 / 54 (7.41%)
    10 / 180 (5.56%)
    4 / 65 (6.15%)
         occurrences all number
    2
    4
    10
    4
    Ear infection
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 54 (0.00%)
    7 / 180 (3.89%)
    3 / 65 (4.62%)
         occurrences all number
    5
    0
    10
    5
    Exanthema subitum
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 54 (1.85%)
    6 / 180 (3.33%)
    2 / 65 (3.08%)
         occurrences all number
    3
    1
    6
    2
    Gastroenteritis viral
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 54 (5.56%)
    5 / 180 (2.78%)
    1 / 65 (1.54%)
         occurrences all number
    1
    3
    5
    1
    Nasopharyngitis
         subjects affected / exposed
    11 / 61 (18.03%)
    9 / 54 (16.67%)
    31 / 180 (17.22%)
    11 / 65 (16.92%)
         occurrences all number
    25
    13
    59
    21
    Influenza
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 54 (1.85%)
    7 / 180 (3.89%)
    2 / 65 (3.08%)
         occurrences all number
    4
    1
    9
    4
    Otitis media
         subjects affected / exposed
    7 / 61 (11.48%)
    3 / 54 (5.56%)
    12 / 180 (6.67%)
    2 / 65 (3.08%)
         occurrences all number
    9
    3
    14
    2
    Pharyngitis
         subjects affected / exposed
    2 / 61 (3.28%)
    5 / 54 (9.26%)
    10 / 180 (5.56%)
    3 / 65 (4.62%)
         occurrences all number
    2
    9
    15
    4
    Pneumonia
         subjects affected / exposed
    5 / 61 (8.20%)
    0 / 54 (0.00%)
    6 / 180 (3.33%)
    1 / 65 (1.54%)
         occurrences all number
    6
    0
    7
    1
    Respiratory tract infection viral
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 54 (1.85%)
    8 / 180 (4.44%)
    4 / 65 (6.15%)
         occurrences all number
    5
    3
    16
    8
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 61 (4.92%)
    5 / 54 (9.26%)
    11 / 180 (6.11%)
    3 / 65 (4.62%)
         occurrences all number
    3
    6
    14
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 54 (0.00%)
    3 / 180 (1.67%)
    3 / 65 (4.62%)
         occurrences all number
    0
    0
    5
    5
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    4 / 61 (6.56%)
    4 / 54 (7.41%)
    8 / 180 (4.44%)
    0 / 65 (0.00%)
         occurrences all number
    5
    4
    9
    0
    Malnutrition
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 54 (1.85%)
    4 / 180 (2.22%)
    3 / 65 (4.62%)
         occurrences all number
    0
    1
    4
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2018
    Introduced the collection of additional visual function data following EU national scientific advice meeting
    10 Jul 2019
    Included the requirement of masked VA assessments to be performed at the 5th birthday visit, following a request from the EMA.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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