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

    Summary
    EudraCT number
    		 2012-005418-20
    Trial protocol
    		 SK   IT   GB   LV   HU   CZ   IE   ES   BE   NL   DE   FR  
    Global end of trial date
    09 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2016
    First version publication date
    25 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRFB002G2302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01846299
    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 x,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 x,
    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
    09 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2015
    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 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 ME. The primary objective 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. 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
    10 Oct 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: 15
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czech Republic: 11
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Latvia: 12
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Turkey: 7
    Worldwide total number of subjects
    178
    EEA total number of subjects
    107
    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)
    89
    From 65 to 84 years
    81
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 181 participants were enrolled. Of these, 178 adults were randomized in a 2:1 ratio and considered for analysis. Additionally, the study included 3 adolescent participants, non-randomized, who received open-label treatment and were not included in the analyses.

    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
    		 Subject, Investigator, Monitor, Data analyst, Carer, 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
    Lucentis
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.5 mg ranibizumab intravitreal injection to the study eye at baseline, and then as needed based on evidence of disease activity

    Arm title
    		 Sham
    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
    Started
    118
    60
    Completed
    106
    50
    Not completed
    12
    10
         Adverse event, serious fatal
    1
    2
         Consent withdrawn by subject
    1
    6
         Physician decision
    4
    2
         Adverse event, non-fatal
    2
    -
         Protocol deviation
    1
    -
         Lost to follow-up
    3
    -

    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
    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 Total
    Number of subjects
    		 118 60 178
    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)
    		 52 37 89
        From 65-84 years
    		 62 19 81
        85 years and over
    		 4 4 8
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 63.5 ± 13.97 61.8 ± 15.55 -
    Gender, Male/Female
    Units: Participants
        Female
    		 45 23 68
        Male
    		 73 37 110

    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
    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 with ranibizumab
    Subject analysis set type
    		 Full analysis
    Subject analysis set 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 with ranibizumab
    Subject analysis set type
    		 Full analysis
    Subject analysis set 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.

    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.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set

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

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    End point title
    		 Change from baseline in best-corrected visual acuity (BCVA) in study eye [1]
    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. A positive change from baseline indicated improvement.
    End point type
    Primary
    End point timeframe
    Baseline, Month 2
    Notes
    [1] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: letters
        least squares mean (standard error)
    5.7 ± 0.81
    2.9 ± 0.89
    Statistical analysis title
    		 Change from baseline in BCVA in the study eye
    Comparison groups
    Ranibizumab v Sham with ranibizumab
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0111
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 5.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.203

    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 [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. A positive change from baseline indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 1, Month 2
    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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: letters
    least squares mean (standard error)
        Month 1 (n=116,59)
    4.7 ± 0.7
    1.4 ± 0.98
        Month 2 (n=114,59)
    5.8 ± 0.76
    2.8 ± 1.05
    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 [3]
    End point description
    CSFT wasassessed 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
    Notes
    [3] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: micrometers (um)
    arithmetic mean (standard deviation)
        Month 1 (n=112,59)
    -83.6 ± 127.45
    -14.3 ± 97.36
        Month 2 (n=112,59)
    -82.5 ± 140.06
    -30.6 ± 102.77
        Month 3 (n=113,59)
    -86.5 ± 136.43
    -92.2 ± 129.85
        Month 4 (n=109,57)
    -94.5 ± 141.55
    -95.5 ± 140.68
        Month 5 (n=105,57)
    -98.6 ± 136.28
    -107.6 ± 142.22
        Month 6 (n=109,54)
    -110.6 ± 133.1
    -84.1 ± 137.86
        Month 7 (n=105,52)
    -113.3 ± 130.84
    -112.9 ± 148.13
        Month 8 (n=105,51)
    -113.1 ± 127.11
    -107.7 ± 157.4
        Month 9 (n=105,52)
    -111.6 ± 127.99
    -116.3 ± 146.43
        Month 10 (n=103,50)
    -114.1 ± 131.12
    -116.6 ± 147.26
        Month 11 (n=101,49)
    -112.1 ± 124
    -123.5 ± 140.65
        Month 12 (n=103,50)
    -121 ± 124.67
    -116.8 ± 137.99
    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 [4]
    End point description
    CSFV was assessed OCT. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
    Notes
    [4] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: microliters (ul)
    arithmetic mean (standard deviation)
        Month 1 (n=112,59)
    -0.296 ± 0.457
    -0.032 ± 0.3969
        Month 2 (n=112,59)
    -0.276 ± 0.5362
    -0.104 ± 0.3958
        Month 3 (n=113,59)
    -0.322 ± 0.5812
    -0.348 ± 0.5075
        Month 4 (n=109,57)
    -0.333 ± 0.5568
    -0.378 ± 0.5436
        Month 5 (n=105,57)
    -0.383 ± 0.5592
    -0.401 ± 0.5893
        Month 6 (n=109,54)
    -0.388 ± 0.5167
    -0.344 ± 0.553
        Month 7 (n=105,52)
    -0.438 ± 0.5267
    -0.438 ± 0.6098
        Month 8 (n=105,51)
    -0.405 ± 0.5074
    -0.421 ± 0.6484
        Month 9 (n=105,52)
    -0.446 ± 0.6066
    -0.444 ± 0.621
        Month 10 (n=103,50)
    -0.439 ± 0.6241
    -0.433 ± 0.6407
        Month 11 (n=101,49)
    -0.406 ± 0.4871
    -0.459 ± 0.6157
        Month 12 (n=103,50)
    -0.447 ± 0.4837
    -0.455 ± 0.591
    No statistical analyses for this end point

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

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    End point title
    		 Number of participants with presence or absence of intra-retinal fluid in study eye compared to baseline [5]
    End point description
    The presence of intra-retinal fluid was assessed by OCT.
    End point type
    Secondary
    End point timeframe
    Month 2, Month 6, Month 12
    Notes
    [5] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: Participants
        Month 2, Absent (n=112,59)
    98
    46
        Month 2, Definite (n=112,59)
    14
    13
        Month 6, Absent (n=109,55)
    97
    43
        Month 6, Definite (n=109,55)
    12
    12
        Month 12, Absent (n=103,50)
    78
    39
        Month 12, Definite (n=103,50)
    25
    11
    No statistical analyses for this end point

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

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    End point title
    		 Number of participants with presence or absence of subretinal fluid in study eye compared to baseline [6]
    End point description
    The presence of subretinal fluid was assessed by OCT.
    End point type
    Secondary
    End point timeframe
    Month 2, Month 6, Month 12
    Notes
    [6] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: Participants
        Month 2, Absent (n=113,59)
    77
    33
        Month 2, Definite (n=110,55)
    36
    26
        Month 6, Absent (n=109,55)
    75
    35
        Month 6, Definite (n=109,55)
    35
    20
        Month 12, Absent (n=104,50)
    77
    37
        Month 12, Definite (n=103,50)
    27
    13
    No statistical analyses for this end point

    Secondary: Number of participants with presence of active macular edema (ME) leakage

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    End point title
    		 Number of participants with presence of active macular edema (ME) leakage [7]
    End point description
    The presence of active ME leakage was assessed by fluorescein angiography (FA).
    End point type
    Secondary
    End point timeframe
    Month 2
    Notes
    [7] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: Participants
    96
    53
    No statistical analyses for this end point

    Secondary: Number of participants requiring rescue treatment at Month 1

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    End point title
    		 Number of participants requiring rescue treatment at Month 1 [8]
    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
    Notes
    [8] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: Participants
    0
    0
    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 [9]
    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. 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
    Notes
    [9] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: letters
    arithmetic mean (standard deviation)
        Average change from BL, month 1 through month 6
    6.39 ± 8.405
    4.5 ± 8.095
        Average change from BL, month 1 through month 12
    7.4 ± 9.052
    5.82 ± 8.927
    No statistical analyses for this end point

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

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    End point title
    		 Proportion of patients with ≥ 1, ≥ 5, ≥ 10 and ≥ 15 letters gain or reaching 84 letters [10]
    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
    Notes
    [10] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: Participants
        Month 2, Gain of >= 15 letters (n=114,59)
    26
    7
        Month 2, Gain of >= 10 letters (n=114,59)
    35
    11
        Month 2, Gain of >= 5 letters (n=114,59)
    55
    19
        Month 2, Gain of >= 1 letter (n=114,59)
    80
    38
        Month 6, Gain of >= 15 letters (n=111,55)
    30
    15
        Month 6, Gain of >= 10 letters (n=111,55)
    41
    21
        Month 6, Gain of >= 5 letters (n=111,55)
    67
    34
        Month 6, Gain of >= 1 letters (n=111,55)
    87
    40
        Month 12, Gain of >= 15 letters (n=106,50)
    44
    22
        Month 12, Gain of >= 10 letters (n=106,50)
    55
    27
        Month 12, Gain of >= 5 letters (n=106,50)
    72
    37
        Month 12, Gain of >= 1 letters (n=106,50)
    86
    42
    No statistical analyses for this end point

    Secondary: Porportion of patients with > 1, > 5, > 10 and > 15 letters loss

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    End point title
    		 Porportion of patients with > 1, > 5, > 10 and > 15 letters loss [11]
    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
    Notes
    [11] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab
    Number of subjects analysed
    117
    60
    Units: Participants
        Month 2, Loss of >1 letter (n=114,59)
    17
    9
        Month 2, Loss of >5 letters (n=114,59)
    8
    4
        Month 2, Loss of >10 letters (n=114,59)
    2
    3
        Month 2, Loss of >15 letters (n=114,59)
    0
    0
        Month 6, Loss of >1 letter (n=111,55)
    14
    12
        Month 6, Loss of >5 letters (n=111,55)
    5
    7
        Month 6, Loss of >10 letters (n=111,55)
    3
    4
        Month 6, Loss of >15 letters (n=111,55)
    1
    1
        Month 12, Loss of >= 1 letter (n=106,50)
    10
    5
        Month 12, Loss of >= 5 letters (n=106,50)
    6
    3
        Month 12, Loss of >= 10 letters (n=106,50)
    2
    3
        Month 12, Loss of >= 15 letters (n=106,50)
    1
    2
    No statistical analyses for this end point

    Secondary: Number of participants with ranibizumab treatments

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    End point title
    		 Number of participants with ranibizumab treatments [12]
    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
    Notes
    [12] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab Sham without ranibizumab
    Number of subjects analysed
    118
    56
    2
    Units: Participants
        Frequency of injections = 0
    0
    0
    2
        Frequency of injections = 1
    13
    6
    0
        Frequency of injections = 2
    5
    3
    0
        Frequency of injections = 3
    14
    7
    0
        Frequency of injections = 4
    3
    5
    0
        Frequency of injections = 5
    17
    7
    0
        Frequency of injections = 6
    7
    11
    0
        Frequency of injections = 7
    6
    0
    0
        Frequency of injections = 8
    13
    0
    0
        Frequency of injections = 9
    3
    6
    0
        Frequency of injections = 10
    12
    11
    0
        Frequency of injections = 11
    6
    0
    0
        Frequency of injections = 12
    20
    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 [13]
    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 6, Month 12
    Notes
    [13] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab Sham without ranibizumab
    Number of subjects analysed
    118
    56
    2
    Units: Participants
        Month 6, Frequency of re-treatment = 1
    34
    15
    0
        Month 6, Frequency of re-treatment = 2
    15
    3
    0
        Month 12, Frequency of re-treatment = 1
    21
    12
    0
        Month 12, Frequency of re-treatment = 2
    24
    7
    0
        Month 12, Frequency of re-treatment = 3
    13
    5
    0
        Month 12, Frequency of re-treatment = 4
    5
    5
    0
        Month 12, Frequency of re-treatment = 5
    3
    0
    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 [14]
    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
    12 months
    Notes
    [14] - 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: All arms do not apply to the end point.
    End point values
    		 Ranibizumab Sham with ranibizumab Sham without Ranibizumab
    Number of subjects analysed
    118
    56
    2
    Units: Participants
        Vision impairment
    38
    22
    0
        OCT abnormality
    637
    345
    1
        FA abnormality
    11
    5
    0
        Color fundus photography abnormality
    0
    0
    0
        Clinical abnormality
    3
    0
    0
        Without documentation (missing reason)
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All other adverse events are monitored from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    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
    15 / 119 (12.61%)
    6 / 56 (10.71%)
    1 / 2 (50.00%)
         number of deaths (all causes)
    1
    1
    1
         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 / 56 (1.79%)
    0 / 2 (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
    Malignant melanoma
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 56 (1.79%)
    0 / 2 (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
    Meningioma benign
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 56 (1.79%)
    0 / 2 (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
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Hypothermia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Atelectasis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    2 / 119 (1.68%)
    0 / 56 (0.00%)
    0 / 2 (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
    Investigations
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Shunt stenosis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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 / 56 (0.00%)
    0 / 2 (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
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 56 (1.79%)
    0 / 2 (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
    Nervous system disorders
    Basilar artery thrombosis
         subjects affected / exposed
    0 / 119 (0.00%)
    0 / 56 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain stem stroke
         subjects affected / exposed
    0 / 119 (0.00%)
    0 / 56 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Dizziness
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Presyncope
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Conjunctivitis allergic (Fellow treated eye)
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Conjunctivitis allergic (Study eye)
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Corneal oedema (Fellow treated eye)
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 56 (1.79%)
    0 / 2 (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
    Open angle glaucoma (Fellow untreated eye)
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Open angle glaucoma (Study eye)
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Gastritis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 56 (1.79%)
    0 / 2 (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
    Intestinal obstruction
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Pancreatitis acute
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 56 (1.79%)
    0 / 2 (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
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Dysuria
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 56 (1.79%)
    0 / 2 (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
    Nephrolithiasis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Urinary tract obstruction
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Musculoskeletal and connective tissue disorders
    Mobility decreased
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 56 (1.79%)
    0 / 2 (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
    Muscular weakness
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 56 (1.79%)
    0 / 2 (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
    Endophthalmitis (Study eye)
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Herpes zoster cutaneous disseminated
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Pneumonia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 56 (0.00%)
    0 / 2 (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
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 56 (1.79%)
    0 / 2 (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
    58 / 119 (48.74%)
    21 / 56 (37.50%)
    0 / 2 (0.00%)
    Investigations
    Intraocular pressure increased (Study eye)
         subjects affected / exposed
    6 / 119 (5.04%)
    3 / 56 (5.36%)
    0 / 2 (0.00%)
         occurrences all number
    9
    6
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 119 (5.04%)
    2 / 56 (3.57%)
    0 / 2 (0.00%)
         occurrences all number
    7
    3
    0
    Eye disorders
    Conjunctival haemorrhage (Study eye)
         subjects affected / exposed
    11 / 119 (9.24%)
    7 / 56 (12.50%)
    0 / 2 (0.00%)
         occurrences all number
    16
    10
    0
    Cystoid macular oedema (Study eye)
         subjects affected / exposed
    6 / 119 (5.04%)
    0 / 56 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    7
    0
    0
    Dry eye (Study eye)
         subjects affected / exposed
    6 / 119 (5.04%)
    1 / 56 (1.79%)
    0 / 2 (0.00%)
         occurrences all number
    6
    1
    0
    Eye pain (Study eye)
         subjects affected / exposed
    10 / 119 (8.40%)
    2 / 56 (3.57%)
    0 / 2 (0.00%)
         occurrences all number
    11
    2
    0
    Macular oedema (Fellow untreated eye)
         subjects affected / exposed
    1 / 119 (0.84%)
    3 / 56 (5.36%)
    0 / 2 (0.00%)
         occurrences all number
    1
    3
    0
    Macular oedema (Study eye)
         subjects affected / exposed
    7 / 119 (5.88%)
    2 / 56 (3.57%)
    0 / 2 (0.00%)
         occurrences all number
    8
    5
    0
    Visual acuity reduced (Study eye)
         subjects affected / exposed
    11 / 119 (9.24%)
    3 / 56 (5.36%)
    0 / 2 (0.00%)
         occurrences all number
    15
    3
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    6 / 119 (5.04%)
    3 / 56 (5.36%)
    0 / 2 (0.00%)
         occurrences all number
    9
    4
    0
    Nasopharyngitis
         subjects affected / exposed
    12 / 119 (10.08%)
    2 / 56 (3.57%)
    0 / 2 (0.00%)
         occurrences all number
    15
    2
    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
    The alignment of the protocol-specified retreatment criteria with current medical practice for the management of patients with visual impairment due to ME, specifically the inclusion of anatomical parameters in addition to BCVA. The optional test, electroretinography (ERG), was removed based on expert feedback. The eligibility criteria for patients with rare diseases were clarified to improve the quality of the patient population by 1) excluding patients with diseases and conditions that were known to spontaneously resolve and/or those in which the use of VEGF inhibitors is controversial and 2) allowed the inclusion of patients with other diseases and conditions that could potentially benefit from treatment with ranibizumab.
    31 Mar 2015
    Error was corrected in Section on Prior and concomitant treatment from “During the study, the use of topical corticosteroids and NSAIDs in the study eye to treat an active ocular condition other than the CNV is permitted” to “…other than the ME is permitted”. Section on risks and benefits was updated. Several typo corrections together with an administrative update were implemented.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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