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    Clinical Trial Results:
    RAINBOW study: a randomized, controlled study evaluating the efficacy and safety of RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity

    Summary
    EudraCT number
    		 2014-003041-10
    Trial protocol
    		 IT   EE   LT   HU   BE   AT   DE   GB   HR   FR   SK   CZ   GR   DK   FI   PL  
    Global end of trial date
    14 Dec 2017

    Results information
    Results version number
    		 v1
    This version publication date
    21 Jun 2018
    First version publication date
    21 Jun 2018
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    CRFB002H2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02375971
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000527-PIP04-13
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate that intravitreal ranibizumab 0.2 mg had superior efficacy to laser therapy in the treatment of retinopathy of prematurity (ROP) as measured by the absence of active ROP and absence of unfavorable structural outcomes in both eyes 24 weeks after starting study treatment.
    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
    30 Dec 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Egypt: 3
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    India: 29
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Japan: 29
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Saudi Arabia: 1
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Turkey: 14
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    225
    EEA total number of subjects
    93
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    225
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 87 sites: Austria(2), Belgium(2), Croatia(2), Czech Republic(3), Denmark(1), Egypt(1), Estonia(1), France(2), Germany(2), Greece(3), Hungary(2), India(6), Italy(4), Japan(17), Lithuania(1), Malaysia(2), Mexico(1), Poland(2), Romania(3), Russia(5), Saudi Arabia(1), Slovakia(1), Taiwan(2), Turkey(6), UK(3) and USA(12).

    Pre-assignment
    Screening details
    		 One patient was discontinued prior to receiving any study treatment and was later re-randomized; this patient is counted twice in the Randomized Set (FAS) (225). The number of unique participants randomized in the study is 224.

    Period 1
    Period 1 title
    Treatment (Day 1 - Baseline)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    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
    Solution for 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
    Solution for 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 therapy (eye)

    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
    74
    77
    74
    Safety Set
    73
    76
    69
    VEGF Set
    19 [1]
    26 [2]
    51 [3]
    PK Set
    49 [4]
    46 [5]
    0 [6]
    Completed
    73
    76
    69
    Not completed
    1
    1
    5
         Subj/Guardian Decision
    -
    -
    2
         Physician decision
    1
    1
    1
         Adverse event, non-fatal
    -
    -
    1
         Lost to follow-up
    -
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients in ‘Started’ = All randomized patients to whom treatment had been assigned (FAS). Patients in ‘Safety Set’ = At least 1 application of investigational treatment and a 1 post baseline safety assessment. Patients in ‘VEGF Set’ = All patients who provided valid Vascular endothelial growth factor (VEGF) plasma samples. Patients in ‘PK Set’ = All patients who provided Pharmacokinetics (PK) serum samples. Patients in ‘Completed’ = All patients who completed the treatment phase.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients in ‘Started’ = All randomized patients to whom treatment had been assigned (FAS). Patients in ‘Safety Set’ = At least 1 application of investigational treatment and a 1 post baseline safety assessment. Patients in ‘VEGF Set’ = All patients who provided valid Vascular endothelial growth factor (VEGF) plasma samples. Patients in ‘PK Set’ = All patients who provided Pharmacokinetics (PK) serum samples. Patients in ‘Completed’ = All patients who completed the treatment phase.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients in ‘Started’ = All randomized patients to whom treatment had been assigned (FAS). Patients in ‘Safety Set’ = At least 1 application of investigational treatment and a 1 post baseline safety assessment. Patients in ‘VEGF Set’ = All patients who provided valid Vascular endothelial growth factor (VEGF) plasma samples. Patients in ‘PK Set’ = All patients who provided Pharmacokinetics (PK) serum samples. Patients in ‘Completed’ = All patients who completed the treatment phase.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients in ‘Started’ = All randomized patients to whom treatment had been assigned (FAS). Patients in ‘Safety Set’ = At least 1 application of investigational treatment and a 1 post baseline safety assessment. Patients in ‘VEGF Set’ = All patients who provided valid Vascular endothelial growth factor (VEGF) plasma samples. Patients in ‘PK Set’ = All patients who provided Pharmacokinetics (PK) serum samples. Patients in ‘Completed’ = All patients who completed the treatment phase.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients in ‘Started’ = All randomized patients to whom treatment had been assigned (FAS). Patients in ‘Safety Set’ = At least 1 application of investigational treatment and a 1 post baseline safety assessment. Patients in ‘VEGF Set’ = All patients who provided valid Vascular endothelial growth factor (VEGF) plasma samples. Patients in ‘PK Set’ = All patients who provided Pharmacokinetics (PK) serum samples. Patients in ‘Completed’ = All patients who completed the treatment phase.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Patients in ‘Started’ = All randomized patients to whom treatment had been assigned (FAS). Patients in ‘Safety Set’ = At least 1 application of investigational treatment and a 1 post baseline safety assessment. Patients in ‘VEGF Set’ = All patients who provided valid Vascular endothelial growth factor (VEGF) plasma samples. Patients in ‘PK Set’ = All patients who provided Pharmacokinetics (PK) serum samples. Patients in ‘Completed’ = All patients who completed the treatment phase.
    Period 2
    Period 2 title
    Follow-Up Phase (up to Day 169)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    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
    Solution for 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
    Solution for 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 therapy (eye)

    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
    73
    76
    69
    Completed
    66
    71
    64
    Not completed
    7
    5
    5
         Adverse event, serious fatal
    4
    4
    4
         Withdrawal of Consent
    1
    1
    -
         Adverse event, non-fatal
    1
    -
    -
         Subject/Guardian Decision
    1
    -
    1

    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
    		 74 77 74 225
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 74 77 74 225
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        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
    Gestational age at birth (weeks)
    Units: Weeks
        arithmetic mean (standard deviation)
    		 25.8 ± 2.25 26.5 ± 2.57 26.2 ± 2.59 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 41 40 37 118
        Male
    		 33 37 37 107
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 27 22 23 72
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 4 3 7
        White
    		 43 45 45 133
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 4 6 3 13

    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: Percentage of Participants with absence of active ROP and absence of unfavorable structural outcomes in both eyes at Week 24

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    End point title
    		 Percentage of Participants with absence of active ROP and absence of unfavorable structural outcomes in both eyes at Week 24
    End point description
    To achieve this outcome, patients must fulfill all the following criteria, 1) survival, 2) no intervention with a second modality for ROP, 3) absence of active ROP and 4) absence of unfavorable structural outcome. Retinopathy of prematurity (ROP) is a pathologic process that occurs in the incompletely vascularized, developing retina of low birth-weight preterm neonates.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    74
    77
    74
    Units: Percentage of Participants
        number (not applicable)
    80.0
    75.0
    66.2
    Statistical analysis title
    		 Primary objective
    Comparison groups
    Ranibizumab 0.2 mg v Ranibizumab 0.1 mg v Laser therapy
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.0254
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9932
         upper limit
    		 4.8235
    Notes
    [1] - The primary efficacy variable was treatment success, defined as the absence of active ROP and absence of unfavorable structural outcomes in both eyes 24 weeks after starting study treatment.

    Secondary: Percentage of Participants requiring Interventions with a second modality for ROP at Week 24

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    End point title
    		 Percentage of Participants requiring Interventions with a second modality for ROP at Week 24
    End point description
    Intervention for ROP in either eye at or before the 24-week assessment visit with a treatment modality other than the modality of the first study treatment. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    74
    77
    74
    Units: Percentage of participants
        number (not applicable)
    14.9
    16.9
    24.3
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing an Event, from the first study treatment to the last study visit

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    End point title
    		 Number of Participants Experiencing an Event, from the first study treatment to the last study visit
    End point description
    An event was defined as death, treatment switch, or the first occurrence of unfavorable structural outcomes in either eye. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Day 1 (after initiation of study treatment) up to study exit (Day 169)
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    74
    77
    74
    Units: Participants
    14
    18
    23
    No statistical analyses for this end point

    Secondary: Percentage of Participants having recurrent ROP and receiving any post-baseline intervention at or before Week 24

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    End point title
    		 Percentage of Participants having recurrent ROP and receiving any post-baseline intervention at or before Week 24
    End point description
    Recurrence of ROP is defined as subjects receiving any post-baseline intervention in either eye at or before 24 weeks (ranibizumab re-treatment or switch to laser in the ranibizumab groups, switch to ranibizumab treatment in the laser group). Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    74
    77
    74
    Units: Percentage of participants
    number (not applicable)
        All participants|
    31.1
    31.2
    18.9
        ZONE I|
    35.7
    53.3
    28.6
        ZONE II|
    28.3
    17.4
    13.0
    No statistical analyses for this end point

    Secondary: Number of Ocular Adverse Events by Primary System Organ (SOCs) at Week 24

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    End point title
    		 Number of Ocular Adverse Events by Primary System Organ (SOCs) at Week 24
    End point description
    Number of Ocular Adverse Events regardless of Study Treatment and Procedure Relationship by Primary System Organ (SOCs) reported categorically (Mild, Moderate, Severe) 24 weeks after the first study treatment. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    73
    76
    69
    Units: Ocular Adverse Events (AEs)
    number (not applicable)
        Mild|
    23.3
    32.9
    17.4
        Moderate|
    4.1
    6.6
    13.0
        Severe|
    2.7
    1.3
    2.9
    No statistical analyses for this end point

    Secondary: Mean change in Ranibizumab concentration in Pharmacokinetic serum samples over time at Day 1, Day 15 and Day 29

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    End point title
    		 Mean change in Ranibizumab concentration in Pharmacokinetic serum samples over time at Day 1, Day 15 and Day 29 [2]
    End point description
    Blood samples for the determination of ranibizumab concentrations were collected in the Ranibizumab treatment arms only at the following time points: within 24 hours after the first administration of ranibizumab, at Day 15 and at Day 29. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 15 and Day 29
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Blood samples for the determination of ranibizumab concentrations were collected in the Ranibizumab treatment arms only.
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg
    Number of subjects analysed
    49 [3]
    46 [4]
    Units: picogram/milliliter (pg/mL)
    arithmetic mean (standard deviation)
        Day 1 (Baseline) (n=43,43)|
    24700.0 ± 52400.00
    12100.0 ± 25500.0
        Day 15 (n=45,36)|
    5830.0 ± 4750.0
    27700.0 ± 144000
        Day 29 (n=31,24)|
    1810.0 ± 2990.0
    732.0 ± 535.0
    Notes
    [3] - n = number of participants in the PK set.
    [4] - n = number of participants in the PK set.
    No statistical analyses for this end point

    Secondary: Mean change in Vascular Endothelial Growth Factor (VEGF) levels over time at Day 1, Day 15 and Day 29

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    End point title
    		 Mean change in Vascular Endothelial Growth Factor (VEGF) levels over time at Day 1, Day 15 and Day 29
    End point description
    Blood samples for the determination of systemic VEGF levels were collected at the following time points: before the first investigational treatment, at Day 15 and at Day 29. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 15 and Day 29
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    19 [5]
    26 [6]
    51 [7]
    Units: picogram/milliliter (pg/mL)
    arithmetic mean (standard deviation)
        Day 1 (n=17,21,46)|
    239.0 ± 226.0
    230.0 ± 224.0
    232.0 ± 240.0
        D1 / no treatment modality switch (n=17,18,41)|
    239.0 ± 226.0
    239.0 ± 233.0
    233.0 ± 245.0
        Day 15 (n=15,26,44)|
    466.0 ± 1500.0
    118.0 ± 129.0
    180.0 ± 214.0
        D15 / no treatment modality switch (n=14,23,38)|
    498.0 ± 1560.0
    124.0 ± 134.0
    177.0 ± 224.0
        Day 29 (n=13,18,30)|
    117.0 ± 84.0
    176.0 ± 142.0
    161.0 ± 132.0
        D29 / no treatment modality switch (n=13,15,27)|
    117.0 ± 84.0
    139.0 ± 75.3
    163.0 ± 138.0
    Notes
    [5] - n = number of participants in the VEGF Set.
    [6] - n = number of participants in the VEGF Set.
    [7] - n = number of participants in the VEGF Set.
    No statistical analyses for this end point

    Secondary: Total Number of Ranibizumab Injections received at Week 24

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    End point title
    		 Total Number of Ranibizumab Injections received at Week 24
    End point description
    Patients randomized to receive Ranibizumab 0.1 mg or 0.2 mg received a single dose of intravitreal Ranibizumab to each eye on Day 1 (Baseline). Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    73
    76
    69
    Units: Injections
    73
    76
    13
    No statistical analyses for this end point

    Secondary: Number of Non-Ocular Adverse Events by Primary System Organ (SOCs) at Week 24

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    End point title
    		 Number of Non-Ocular Adverse Events by Primary System Organ (SOCs) at Week 24
    End point description
    Number of Non-Ocular Adverse Events regardless of Study Treatment and Procedure Relationship by Primary System Organ (SOCs) reported categorically (Mild, Moderate, Severe) 24 weeks after the first study treatment. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    73
    76
    69
    Units: Non-Ocular Adverse Events (AEs)
    number (not applicable)
        Mild|
    37.0
    27.6
    31.9
        Moderate|
    24.7
    34.2
    27.5
        Severe|
    23.3
    19.7
    17.4
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Vital signs (Body Length, Head Circumference and Knee to Heel Length) at Day 85 and Day 169

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    End point title
    		 Mean change from Baseline in Vital signs (Body Length, Head Circumference and Knee to Heel Length) at Day 85 and Day 169
    End point description
    Body Length, Head Circumference and Knee to Heel Length were assessed. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85, Day 169
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    73 [8]
    76 [9]
    69 [10]
    Units: centimeter (cm)
    arithmetic mean (standard deviation)
        Day 85 / Body Length (n=61,63,60)|
    10.1 ± 2.59
    11.0 ± 3.33
    11.1 ± 3.65
        Day 169 / Body Length (n=62,62,57)|
    18.7 ± 3.28
    18.6 ± 3.66
    19.0 ± 4.50
        Day 85 / Head Circumference (n=62,62,59)|
    6.9 ± 1.96
    6.5 ± 2.31
    7.2 ± 2.13
        Day 169 / Head Circumference (n=62,62,57)|
    10.4 ± 2.12
    10.3 ± 2.56
    10.6 ± 2.61
        Day 85 / Knee to Heel Length (n=55,51,52)|
    2.9 ± 1.90
    3.1 ± 1.65
    3.1 ± 2.02
        Day 169 / Knee to Heel Length (n=53,52,52)|
    5.4 ± 2.86
    5.1 ± 2.19
    5.3 ± 2.15
    Notes
    [8] - n = number of participants in the Safety Set.
    [9] - n = number of participants in the Safety Set.
    [10] - n = number of participants in the Safety Set.
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Vital signs (Weight) at Day 85 and Day 169

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    End point title
    		 Mean change from Baseline in Vital signs (Weight) at Day 85 and Day 169
    End point description
    Body weight was measured. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85, Day 169
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    73 [11]
    76 [12]
    69 [13]
    Units: gram (g)
    arithmetic mean (standard deviation)
        Day 85 / Weight (n=63,66,60)|
    2198.9 ± 615.68
    2149.9 ± 754.27
    2182.7 ± 612.70
        Day 169 / Weight (n=62,62,60)|
    3794.3 ± 782.48
    3716.7 ± 897.15
    3826.0 ± 882.17
    Notes
    [11] - n = number of participants in the Safety Set.
    [12] - n = number of participants in the Safety Set.
    [13] - n = number of participants in the Safety Set.
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Vital signs (Sitting Blood Pressure) at Day 85 and Day 169

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    End point title
    		 Mean change from Baseline in Vital signs (Sitting Blood Pressure) at Day 85 and Day 169
    End point description
    Blood Pressure measurements were not required by the protocol. Instead, the most recent Systolic and Diastolic Blood Pressure expressed in millimeters of mercury (mmHg) measured as part of the routine clinical care were used. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85, Day 169
    End point values
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser therapy
    Number of subjects analysed
    73 [14]
    76 [15]
    69 [16]
    Units: millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Day 85 / Sitting Diastolic BP (n=47,46,41)|
    8.1 ± 14.66
    7.0 ± 14.25
    9.8 ± 16.95
        Day 85 / Sitting Systolic BP (n=47,46,41)|
    6.3 ± 15.85
    9.4 ± 15.73
    15.5 ± 16.85
        Day 169 / Sitting Diastolic BP (n=45,46,40)|
    11.5 ± 15.60
    11.8 ± 14.42
    14.7 ± 17.05
        Day 169 / Sitting Systolic BP (n=45,46,40)|
    10.2 ± 16.15
    11.2 ± 13.45
    17.7 ± 19.35
    Notes
    [14] - n = number of participants in the Safety Set.
    [15] - n = number of participants in the Safety Set.
    [16] - n = number of participants in the Safety Set.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Ranibizumab 0.2 mg
    Reporting group description
    		 Ranibizumab 0.2 mg

    Reporting group title
    Ranibizumab 0.1 mg
    Reporting group description
    		 Ranibizumab 0.1 mg

    Reporting group title
    Laser
    Reporting group description
    		 Laser

    Serious adverse events
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 73 (35.62%)
    24 / 76 (31.58%)
    24 / 69 (34.78%)
         number of deaths (all causes)
    4
    4
    4
         number of deaths resulting from adverse events
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haemodynamic instability
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pregnancy, puerperium and perinatal conditions
    Perinatal brain damage
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cyst
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    No adverse event
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Dependence on oxygen therapy
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary dysplasia
         subjects affected / exposed
    2 / 73 (2.74%)
    2 / 76 (2.63%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary vein stenosis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory arrest
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 73 (0.00%)
    3 / 76 (3.95%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    Respiratory symptom
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheomalacia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Breath holding
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychomotor retardation
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood potassium increased
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Greenstick fracture
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileal atresia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral cyst
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nystagmus
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exophthalmos
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinopathy of prematurity
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 76 (1.32%)
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 76 (2.63%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising colitis
         subjects affected / exposed
    0 / 73 (0.00%)
    3 / 76 (3.95%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone disorder
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteopenia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    2 / 73 (2.74%)
    4 / 76 (5.26%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orbital infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 76 (0.00%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Roseola
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    Septic shock
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperphosphatasaemia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Ranibizumab 0.2 mg Ranibizumab 0.1 mg Laser
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 73 (58.90%)
    47 / 76 (61.84%)
    37 / 69 (53.62%)
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    2 / 73 (2.74%)
    5 / 76 (6.58%)
    1 / 69 (1.45%)
         occurrences all number
    2
    7
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 73 (5.48%)
    8 / 76 (10.53%)
    5 / 69 (7.25%)
         occurrences all number
    5
    9
    7
    Anaemia neonatal
         subjects affected / exposed
    2 / 73 (2.74%)
    4 / 76 (5.26%)
    1 / 69 (1.45%)
         occurrences all number
    2
    4
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 73 (12.33%)
    6 / 76 (7.89%)
    4 / 69 (5.80%)
         occurrences all number
    12
    7
    4
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    6 / 73 (8.22%)
    6 / 76 (7.89%)
    2 / 69 (2.90%)
         occurrences all number
    12
    8
    3
    Retinal haemorrhage
         subjects affected / exposed
    6 / 73 (8.22%)
    10 / 76 (13.16%)
    7 / 69 (10.14%)
         occurrences all number
    10
    15
    10
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 73 (0.00%)
    4 / 76 (5.26%)
    0 / 69 (0.00%)
         occurrences all number
    0
    6
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    5
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 73 (6.85%)
    5 / 76 (6.58%)
    4 / 69 (5.80%)
         occurrences all number
    5
    5
    4
    Inguinal hernia
         subjects affected / exposed
    3 / 73 (4.11%)
    0 / 76 (0.00%)
    2 / 69 (2.90%)
         occurrences all number
    3
    0
    2
    Vomiting
         subjects affected / exposed
    2 / 73 (2.74%)
    4 / 76 (5.26%)
    2 / 69 (2.90%)
         occurrences all number
    2
    5
    2
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    1 / 73 (1.37%)
    4 / 76 (5.26%)
    1 / 69 (1.45%)
         occurrences all number
    1
    7
    1
    Bronchopulmonary dysplasia
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 76 (3.95%)
    4 / 69 (5.80%)
         occurrences all number
    2
    3
    4
    Bronchospasm
         subjects affected / exposed
    3 / 73 (4.11%)
    0 / 76 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    3
    0
    1
    Cough
         subjects affected / exposed
    4 / 73 (5.48%)
    2 / 76 (2.63%)
    1 / 69 (1.45%)
         occurrences all number
    4
    2
    1
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    8 / 73 (10.96%)
    6 / 76 (7.89%)
    4 / 69 (5.80%)
         occurrences all number
    10
    6
    4
    Musculoskeletal and connective tissue disorders
    Osteopenia
         subjects affected / exposed
    0 / 73 (0.00%)
    4 / 76 (5.26%)
    1 / 69 (1.45%)
         occurrences all number
    0
    4
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 73 (1.37%)
    6 / 76 (7.89%)
    2 / 69 (2.90%)
         occurrences all number
    2
    11
    4
    Nasopharyngitis
         subjects affected / exposed
    7 / 73 (9.59%)
    5 / 76 (6.58%)
    4 / 69 (5.80%)
         occurrences all number
    7
    8
    6
    Pneumonia
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    6 / 69 (8.70%)
         occurrences all number
    2
    1
    6
    Rhinitis
         subjects affected / exposed
    3 / 73 (4.11%)
    0 / 76 (0.00%)
    2 / 69 (2.90%)
         occurrences all number
    3
    0
    2
    Sepsis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    3 / 69 (4.35%)
         occurrences all number
    2
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 73 (8.22%)
    3 / 76 (3.95%)
    1 / 69 (1.45%)
         occurrences all number
    8
    4
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 73 (4.11%)
    2 / 76 (2.63%)
    2 / 69 (2.90%)
         occurrences all number
    4
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Aug 2015
    Amendment 1: The main purpose of amendment 1 is to: • Include additional safety assessments as requested by Health Authorities and Institutional Review Boards (IRBs)/Independent Ethics Committees during the clinical trial application process. This will enhance the safety monitoring. • Amend the exclusion criteria to improve clarity. The exclusion criteria #2 was deleted because it was redundant with e.g. exclusion 11. The exclusion criteria #11 was amended to clarify that clinically significant comorbidities are exclusionary only if they are assessed by the investigator to have a clinically relevant impact on study participation, any of the study procedures, or on efficacy assessments. • Better align the rescue procedures and criteria with current clinical practice including changes to the definition of ROP disease that is unchanged, has minimally improved or has worsened. • Retain patients in the trial for further follow-up in the instances when they are administered with prohibited treatment. This will ensure an appropriate safety monitoring of these patients.
    01 Feb 2017
    Amendment 2: The main purpose of amendment 2 is to reduce the number from 300 patients planned to be treated in the study to approximately 180 patients planned to be randomized following approval by the European Medicine Agency to modify an agreed Paediatric Investigation Plan (PIP).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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