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    Clinical Trial Results:
    A 12-month, randomized, double-masked, sham-controlled, multicenter study to evaluate the efficacy and safety of 0.5 mg ranibizumab intravitreal injections in patients with visual impairment due to vascular endothelial growth factor (VEGF) driven choroidal neovascularization (CNV)

    Summary
    EudraCT number
    		 2012-005417-38
    Trial protocol
    		 SK   IT   LV   PT   HU   CZ   ES   LT   BE   GR   DK   DE   PL   FR  
    Global end of trial date
    11 Nov 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    17 Jul 2016
    First version publication date
    13 May 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CRFB002G2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01840410
    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,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    11 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate that an individualized regimen of intravitreal injection of 0.5 mg ranibizumab has superior efficacy compared to sham treatment in adult patients with visual impairment due to VEGF-driven CNV. It was assessed by the best-corrected visual acuity (BCVA) change from baseline to Month 2.
    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
    19 Sep 2013
    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
    Australia: 10
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Latvia: 7
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Lithuania: 3
    Country: Number of subjects enrolled
    Peru: 1
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Portugal: 6
    Worldwide total number of subjects
    178
    EEA total number of subjects
    130
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    123
    From 65 to 84 years
    54
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 183 participants were enrolled. Of these, 178 adults were randomized in a 2:1 ratio and considered for analysis. There were 5 adolescent participants, non-randomized, who received open-label treatment and were not included in the analyses. Therefore, the number enrolled = 183 differs from the participant flow number started = 178.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ranibizumab
    Arm description
    		 A 0.5 mg ranibizumab intravitreal injection was given to the study eye at baseline, and then as needed based on evidence of disease activity.
    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
    A 0.5 mg ranibizumab intravitreal injection was given to the study eye at baseline, and then as needed based on evidence of disease activity.

    Arm title
    		 Sham control
    Arm description
    		 Sham injection was given to the study eye at baseline, and then treatment was given based on evidence of disease activity. At Month 1, if treatment was needed, sham was administered. At Month 2, participants could switch to open-label ranibizumab on an as needed basis.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sham
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Sham injection was given to the study eye at baseline, and then treatment was given based on evidence of disease activity. At Month 1, if treatment was needed, sham was administered. At Month 2, participants could switch to open-label ranibizumab on an as needed basis. The sham vial did not contain active drug (empty sterile vial). The sham injection was an imitation of an intravitreal injection using an injection syringe without a needle touching the eye.

    Number of subjects in period 1
    		Ranibizumab Sham control
    Started
    119
    59
    Safety set
    119
    59
    Full analysis set
    119
    59
    Completed
    112
    55
    Not completed
    7
    4
         Consent withdrawn by subject
    2
    1
         Physician decision
    1
    2
         Adverse event, non-fatal
    1
    1
         Protocol deviation
    1
    -
         Pregnancy
    1
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ranibizumab
    Reporting group description
    		 A 0.5 mg ranibizumab intravitreal injection was given to the study eye at baseline, and then as needed based on evidence of disease activity.

    Reporting group title
    Sham control
    Reporting group description
    		 Sham injection was given to the study eye at baseline, and then treatment was given based on evidence of disease activity. At Month 1, if treatment was needed, sham was administered. At Month 2, participants could switch to open-label ranibizumab on an as needed basis.

    Reporting group values
    		 Ranibizumab Sham control Total
    Number of subjects
    		 119 59 178
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 82 41 123
        From 65-84 years
    		 36 18 54
        85 years and over
    		 1 0 1
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.6 ( 15.07 ) 51.9 ( 17.29 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 60 30 90
        Male
    		 59 29 88

    End points

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    End points reporting groups
    Reporting group title
    Ranibizumab
    Reporting group description
    		 A 0.5 mg ranibizumab intravitreal injection was given to the study eye at baseline, and then as needed based on evidence of disease activity.

    Reporting group title
    Sham control
    Reporting group description
    		 Sham injection was given to the study eye at baseline, and then treatment was given based on evidence of disease activity. At Month 1, if treatment was needed, sham was administered. At Month 2, participants could switch to open-label ranibizumab on an as needed basis.

    Subject analysis set title
    Sham without Ranibizumab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants did not receive ranibizumab at any time during the study.

    Primary: Change from baseline in best-corrected visual acuity (BCVA) in study eye to Month 2

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    End point title
    		 Change from baseline in best-corrected visual acuity (BCVA) in study eye to Month 2
    End point description
    BCVA was assessed in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity (VA) testing charts at an initial testing distance of 4 meters. The data were analyzed using mixed model repeated measures (MMRM) which contained scheduled visit, the type of underlying pathophysiologic mechanism (angloid streaks versus others) and treatment group as fixed effect factors, centered baseline BCVA as a continuous covariate and treatment group by visit and visit by centered baseline BCVA interactions. A positive change from baseline indicated improvement.
    End point type
    Primary
    End point timeframe
    Baseline, Month 2
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    118
    57
    Units: letters
        least squares mean (standard error)
    9.5 ( 0.95 )
    -0.4 ( 1.16 )
    Statistical analysis title
    		 Change from baseline in BCVA in study eye
    Comparison groups
    Ranibizumab v Sham control
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    9.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.97
         upper limit
    		 12.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.502

    Secondary: Change from baseline in BCVA in study eye up to Month 2

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    End point title
    		 Change from baseline in BCVA in study eye up to Month 2
    End point description
    BCVA was assessed in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity (VA) testing charts at an initial testing distance of 4 meters. The data were analyzed using analysis of covariance (ANCOVA) model which contained the type of underlying pathophysiologic mechanism (angloid streaks versus others) and treatment group as fixed effect factors, centered baseline BCVA as a continuous covariate. A positive change from baseline indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 1, Month 2
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    118
    57
    Units: letters
    least squares mean (standard error)
        Month 1
    7.1 ( 0.75 )
    0.1 ( 1.08 )
        Month 2
    9.5 ( 0.91 )
    -0.4 ( 1.31 )
    No statistical analyses for this end point

    Secondary: Change from baseline in central subfield thickness (CSFT) in study eye

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    End point title
    		 Change from baseline in central subfield thickness (CSFT) in study eye
    End point description
    CSFT was assessed by optical coherence tomography (OCT). A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    119
    59
    Units: micrometer (um)
    arithmetic mean (standard deviation)
        Month 1 (n=115,56)
    -74.4 ( 81.25 )
    3.3 ( 89.43 )
        Month 2 (n=114,54)
    -76.4 ( 108.24 )
    1.9 ( 119.44 )
        Month 3 (n=114,56)
    -82.9 ( 114.26 )
    -59.1 ( 142.37 )
        Month 4 (n=114,56)
    -83.5 ( 104.71 )
    -68.4 ( 155.26 )
        Month 5 (n=116,55)
    -83.8 ( 112.41 )
    -89.4 ( 130.68 )
        Month 6 (n=112,54)
    -89.1 ( 109.19 )
    -85.9 ( 117.54 )
        Month 7 (n=114,55)
    -83.1 ( 105.97 )
    -84.5 ( 141.36 )
        Month 8 (n=111,55)
    -94.7 ( 111.54 )
    -97.9 ( 118.34 )
        Month 9 (n=110,55)
    -90 ( 112.44 )
    -93.5 ( 113.88 )
        Month 10 (n=108,53)
    -100.5 ( 119.45 )
    -85.4 ( 136.9 )
        Month 11 (n=110,55)
    -99.5 ( 112.38 )
    -82.8 ( 158.78 )
        Month 12 (n=109,55)
    -102.7 ( 117.27 )
    -91.7 ( 152.36 )
    No statistical analyses for this end point

    Secondary: Change from baseline in central subfield volume (CSFV) in study eye

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    End point title
    		 Change from baseline in central subfield volume (CSFV) in study eye
    End point description
    CSFV was assessed OCT. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    119
    59
    Units: microliter (ul)
    arithmetic mean (standard deviation)
        Month 1 (n=115,56)
    -0.354 ( 0.4103 )
    0.012 ( 0.3608 )
        Month 2 (n=114,54)
    -0.357 ( 0.548 )
    -0.006 ( 0.5792 )
        Month 3 (n=114,56)
    -0.369 ( 0.5506 )
    -0.269 ( 0.6583 )
        Month 4 (n=114,56)
    -0.371 ( 0.4798 )
    -0.291 ( 0.7647 )
        Month 5 (n=116,55)
    -0.392 ( 0.5404 )
    -0.381 ( 0.575 )
        Month 6 (n=112,54)
    -0.409 ( 0.5305 )
    -0.375 ( 0.531 )
        Month 7 (n=114,54)
    -0.366 ( 0.4905 )
    -0.374 ( 0.5966 )
        Month 8 (n=110,55)
    -0.414 ( 0.5021 )
    -0.411 ( 0.497 )
        Month 9 (n=110,55)
    -0.404 ( 0.5182 )
    -0.413 ( 0.5251 )
        Month 10 (n=108,53)
    -0.437 ( 0.5506 )
    -0.385 ( 0.5688 )
        Month 11 (n=110,55)
    -0.448 ( 0.5285 )
    -0.352 ( 0.7021 )
        Month 12 (n=109,55)
    -0.441 ( 0.546 )
    -0.378 ( 0.6704 )
    No statistical analyses for this end point

    Secondary: Number of participants with presence of intra-retinal fluid in study eye compared to baseline

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    End point title
    		 Number of participants with presence of intra-retinal fluid in study eye compared to baseline
    End point description
    The presence of intra-retinal fluid was assessed by OCT.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2, Month 6, Month 12
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    119
    59
    Units: Participants
        Baseline, Absent (n=116,56)
    70
    32
        Baseline, Definite (n=116,56)
    46
    24
        Month 2, Absent (n=116,56)
    97
    29
        Month 2, Definite (n=116,56)
    19
    27
        Month 6, Absent (n=116,54)
    100
    43
        Month 6, Definite (n=116,54)
    16
    11
        Month 12, Absent (n=111,55)
    95
    45
        Month 12, Definite (n=111,55)
    16
    10
    No statistical analyses for this end point

    Secondary: Number of participants with presence of subretinal fluid in study eye compared to baseline

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    End point title
    		 Number of participants with presence of subretinal fluid in study eye compared to baseline
    End point description
    Presence of subretinal fluid in study eye compared to baseline
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2, Month 6, Month 12
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    119
    59
    Units: Participants
        Baseline, Absent (n=116,56)
    16
    6
        Baseline, Definite (n=116,56)
    100
    50
        Month 2, Absent (n=116,56)
    72
    11
        Month 2, Definite (n=116,56)
    44
    45
        Month 6, Absent (n=116,54)
    77
    34
        Month 6, Definite (n=116,54)
    39
    20
        Month 12, Absent (n=111,55)
    78
    41
        Month 12, Definite (n=111,55)
    33
    14
    No statistical analyses for this end point

    Secondary: Number of participants with presence of active chorioretinal leakage

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    End point title
    		 Number of participants with presence of active chorioretinal leakage
    End point description
    The presence of active chorioretinal leakage was assessed by photography imaging, i.e. fluorescein angiography (FA).
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2, Month 6, Month 12
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    119
    59
    Units: Participants
        Baseline, Absent (n=106,50)
    2
    1
        Baseline, Definite (n=106,50)
    104
    49
        Month 2, Absent (n=106,50)
    37
    4
        Month 2, Definite (n=106,50)
    69
    46
        Month 6, Absent (n=108,45)
    64
    29
        Month 6, Definite (n=108,45)
    44
    16
        Month 12, Absent (n=103,47)
    81
    37
        Month 12, Definite (n=103,47)
    22
    10
    No statistical analyses for this end point

    Secondary: Average change from baseline in BCVA

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    End point title
    		 Average change from baseline in BCVA
    End point description
    BCVA was assessed in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity (VA) testing charts at an initial testing distance of 4 meters. BCVA was assessed at each month from Month 1 through Month 6 or at each month from Month 1 through month 12, and the data were averaged. The outcome measure is reporting the change between baseline and average BCVA from Month 1 through Month 6 or from Month 1 through Month 12 (average BCVA - baseline BCVA). A positive change from baseline indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (BL), Month 1 through Month 6, Month 1 through Month 12
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    119
    59
    Units: letters
    arithmetic mean (standard deviation)
        Average change from BL, month 1 through month 6
    9.53 ( 10.467 )
    4.68 ( 8.786 )
        Average change from BL, month 1 through month 12
    9.99 ( 11.528 )
    6.59 ( 10.666 )
    No statistical analyses for this end point

    Secondary: Number of participants with ≥ 1, ≥ 5, ≥ 10 and ≥ 15 letters gain or reaching 84 letters

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    End point title
    		 Number of participants with ≥ 1, ≥ 5, ≥ 10 and ≥ 15 letters gain or reaching 84 letters
    End point description
    VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using ETDRS-like visual acuity testing charts at a testing distance of 4 meters.
    End point type
    Secondary
    End point timeframe
    Month 2, Month 6, Month 12
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    119
    59
    Units: Participants
        Month 2,>=15 letters or reaching 85 let.(n=118,57)
    37
    7
        Month 2, >=10 letters (n=118,57)
    50
    8
        Month 2, >=5 letters (n=118,57)
    83
    16
        Month 2, >=1 letter (118,57)
    101
    27
        Month 6,>=15 letters or reaching 85 let.(n=118,54)
    53
    20
        Month 6, >=10 letters (n=118,54)
    67
    24
        Month 6, >= 5 letters (n=118,54)
    88
    34
        Month 6, >= 1 letter (n=118,54)
    104
    39
        Month 12,>=15 letters or reaching 85 let.;n=113,55
    55
    23
        Month 12, >=10 letters (n=113,55)
    64
    28
        Month 12, >=5 letters (n=113,55)
    81
    34
        Month 12, >=1 letter (n=113,55)
    100
    42
    No statistical analyses for this end point

    Secondary: Number of participants with > 1, > 5, > 10 and > 15 letters loss

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    End point title
    		 Number of participants with > 1, > 5, > 10 and > 15 letters loss
    End point description
    VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using ETDRS-like visual acuity testing charts at a testing distance of 4 meters.
    End point type
    Secondary
    End point timeframe
    Month 2, Month 6, Month 12
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    119
    59
    Units: Participants
        Month 2, loss of >1 letter (n=118,57)
    10
    24
        Month 2, loss of >5 letters (n=118,57)
    3
    12
        Month 2, loss of >10 letters (n=118,57)
    1
    5
        Month 2, loss of >15 letters (n=118,57)
    1
    3
        Month 6, loss of >1 letter (n=118,54)
    10
    9
        Month 6, loss of >5 letters (n=118,54)
    7
    5
        Month 6, loss of >10 letters (n=118,54)
    6
    2
        Month 6, loss of >15 letters (n=118,54)
    3
    2
        Month 12, loss of >1 letter (n=113,55)
    9
    10
        Month 12, loss of >5 letters (n=113,55)
    6
    6
        Month 12, loss of >10 letters (n=113,55)
    5
    4
        Month 12,loss of >15 letters (n=113,55)
    3
    2
    No statistical analyses for this end point

    Secondary: Number of participants with requirement for rescue treatment at Month 1

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    End point title
    		 Number of participants with requirement for rescue treatment at Month 1
    End point description
    Rescue treatment with laser photocoagulation or periocular treatment could be administered at Month 1 only if the participant had a visual acuity loss of > 5 letters due to disease activity from baseline to Month 1.
    End point type
    Secondary
    End point timeframe
    Month 1
    End point values
    		 Ranibizumab Sham control
    Number of subjects analysed
    119
    58
    Units: Participants
    0
    1
    No statistical analyses for this end point

    Secondary: Number of participants with ranibizumab treatments in study eye

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    End point title
    		 Number of participants with ranibizumab treatments in study eye
    End point description
    The number of participants administered study treatments, according to treatment frequency, was assessed.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Ranibizumab Sham control Sham without Ranibizumab
    Number of subjects analysed
    119
    52
    7
    Units: Participants
        Frequency of injections = 0
    0
    0
    7
        Frequency of injections = 1
    12
    5
    0
        Frequency of injections = 2
    12
    6
    0
        Frequency of injections = 3
    19
    7
    0
        Frequency of injections = 4
    13
    6
    0
        Frequency of injections = 5
    9
    5
    0
        Frequency of injections = 6
    11
    6
    0
        Frequency of injections = 7
    2
    2
    0
        Frequency of injections = 8
    8
    1
    0
        Frequency of injections = 9
    5
    4
    0
        Frequency of injections = 10
    7
    10
    0
        Frequency of injections = 11
    6
    0
    0
        Frequency of injections = 12
    15
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with re-treatments

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    End point title
    		 Number of participants with re-treatments
    End point description
    The number of participants, administered re-treatments according to treatment frequency, was assessed. Re-treatment was defined as an administration of study medication following at least one non-missed visit where treatment was not administered in the study eye. Up to month 12, the maximum number of retreatments was 5.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Ranibizumab Sham control Sham without Ranibizumab
    Number of subjects analysed
    119
    52
    7
    Units: Paticipants
        Frequency of re-treatment = 1
    25
    21
    0
        Frequency of re-treatment = 2
    22
    10
    0
        Frequency of re-treatment = 3
    9
    4
    0
        Frequency of re-treatment = 4
    5
    2
    0
    No statistical analyses for this end point

    Secondary: Number of primary reasons for decision to treat by Investigator

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    End point title
    		 Number of primary reasons for decision to treat by Investigator
    End point description
    The total number of primary reasons for decisions to treat was assessed. A single participant could have had multiple primary reasons for treatment.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Ranibizumab Sham control Sham without Ranibizumab
    Number of subjects analysed
    119
    52
    7
    Units: Number of primary reasons
        Vision impairment
    29
    9
    0
        OCT abnormality
    522
    306
    1
        FA abnormality
    21
    13
    0
        Color fundus photography abnormality
    1
    0
    0
        Clinical abnormality
    6
    0
    0
        Without documentation
    1
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Ranibizumab 0.5 mg
    Reporting group description
    		 Ranibizumab 0.5 mg

    Reporting group title
    Sham with Ranibizumab 0.5 mg
    Reporting group description
    		 Sham with Ranibizumab 0.5 mg

    Reporting group title
    Sham without Ranibizumab 0.5 mg
    Reporting group description
    		 Sham without Ranibizumab 0.5 mg

    Serious adverse events
    		 Ranibizumab 0.5 mg Sham with Ranibizumab 0.5 mg Sham without Ranibizumab 0.5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 119 (7.56%)
    4 / 52 (7.69%)
    0 / 7 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 52 (1.92%)
    0 / 7 (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
    Intraductal papilloma of breast
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    0 / 7 (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
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    0 / 7 (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
    Pituitary tumour benign
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    0 / 7 (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
    Vascular disorders
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    0 / 7 (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
    Atrial fibrillation
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    0 / 7 (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
    Nervous system disorders
    Parkinsonism
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    0 / 7 (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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 52 (1.92%)
    0 / 7 (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
    Eye disorders
    Retinal detachment (Fellow untreated eye)
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    0 / 7 (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
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    0 / 7 (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
    Faecaloma
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 52 (1.92%)
    0 / 7 (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, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    0 / 7 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 52 (1.92%)
    0 / 7 (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
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 52 (1.92%)
    0 / 7 (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
    Musculoskeletal and connective tissue disorders
    Rheumatic disorder
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 52 (1.92%)
    0 / 7 (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
    Infections and infestations
    Urosepsis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 52 (1.92%)
    0 / 7 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ranibizumab 0.5 mg Sham with Ranibizumab 0.5 mg Sham without Ranibizumab 0.5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 119 (35.29%)
    19 / 52 (36.54%)
    4 / 7 (57.14%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 119 (4.20%)
    1 / 52 (1.92%)
    1 / 7 (14.29%)
         occurrences all number
    5
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 119 (0.84%)
    3 / 52 (5.77%)
    1 / 7 (14.29%)
         occurrences all number
    1
    3
    1
    Eye disorders
    Choroidal neovascularisation (Study eye)
         subjects affected / exposed
    3 / 119 (2.52%)
    0 / 52 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    3
    0
    1
    Conjunctival haemorrhage (Study eye)
         subjects affected / exposed
    7 / 119 (5.88%)
    6 / 52 (11.54%)
    0 / 7 (0.00%)
         occurrences all number
    8
    7
    0
    Eye inflammation (Study eye)
         subjects affected / exposed
    0 / 119 (0.00%)
    0 / 52 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Foreign body sensation in eyes (Study eye)
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 52 (1.92%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    1
    Macular oedema (Study eye)
         subjects affected / exposed
    0 / 119 (0.00%)
    0 / 52 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Ocular hyperaemia (Study eye)
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 52 (1.92%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    1
    Photopsia (Study eye)
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Visual acuity reduced (Study eye)
         subjects affected / exposed
    3 / 119 (2.52%)
    1 / 52 (1.92%)
    1 / 7 (14.29%)
         occurrences all number
    3
    2
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 119 (5.04%)
    0 / 52 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    6
    0
    1
    Infections and infestations
    Conjunctivitis (Study eye)
         subjects affected / exposed
    2 / 119 (1.68%)
    3 / 52 (5.77%)
    0 / 7 (0.00%)
         occurrences all number
    2
    3
    0
    Influenza
         subjects affected / exposed
    9 / 119 (7.56%)
    0 / 52 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    9
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    14 / 119 (11.76%)
    9 / 52 (17.31%)
    1 / 7 (14.29%)
         occurrences all number
    19
    12
    1
    Pneumonia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 52 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Sinusitis
         subjects affected / exposed
    2 / 119 (1.68%)
    3 / 52 (5.77%)
    0 / 7 (0.00%)
         occurrences all number
    2
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2014
    Amendment 1 (04-May-2014) was a substantial amendment and was issued 8 months after study start (when 28 patients were enrolled) and introduced the following changes: protocol-specified retreatment criteria were aligned with current medical practice for the management of patients with visual impairment due to CNV, specifically the inclusion of anatomic parameters, in addition to BCVA; eligibility criteria were revised to exclude two additional CNV conditions that are considered sub-categories of nAMD: 1) PCV and 2) RAP lesions in patients ≥ 50 years of age. The classification of these two CNV conditions as nAMD was not explicitly mentioned in the original protocol, which led to inclusion of some patients with these conditions; and two optional tests, visual field and electroretinography, were removed based on expert feedback.

    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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