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    Clinical Trial Results:
    A 12-month, Phase 3b, randomized, visual acuity assessor-masked, multicenter study assessing the efficacy and safety of ranibizumab 0.5mg in treat and extend regimen compared to monthly regimen, in patients with neovascular age-related macular degeneration

    Summary
    EudraCT number
    		 2013-002626-23
    Trial protocol
    		 ES   IT   BE   DE   SK   GB   HU   PT   DK   SI   HR  
    Global end of trial date
    19 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Nov 2016
    First version publication date
    04 Nov 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CRFB002A2411
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01948830
    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, trialandresults.registries@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 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 the ranibizumab Treat and Extend regimen (TER) was non-inferior to ranibizumab monthly regimen in patients with nAMD as assessed by the change in best corrected visual acuity (BCVA) from Baseline to Month 12.
    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
    17 Dec 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
    Belgium: 15
    Country: Number of subjects enrolled
    Croatia: 34
    Country: Number of subjects enrolled
    Denmark: 22
    Country: Number of subjects enrolled
    Egypt: 10
    Country: Number of subjects enrolled
    Germany: 68
    Country: Number of subjects enrolled
    United Kingdom: 40
    Country: Number of subjects enrolled
    Hungary: 105
    Country: Number of subjects enrolled
    India: 11
    Country: Number of subjects enrolled
    Israel: 50
    Country: Number of subjects enrolled
    Italy: 44
    Country: Number of subjects enrolled
    Korea, Republic of: 28
    Country: Number of subjects enrolled
    Portugal: 38
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    Slovakia: 49
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Spain: 56
    Country: Number of subjects enrolled
    Switzerland: 26
    Country: Number of subjects enrolled
    Turkey: 12
    Worldwide total number of subjects
    650
    EEA total number of subjects
    473
    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)
    78
    From 65 to 84 years
    483
    85 years and over
    89

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients were randomized 1:1 into one of two treatment arms, Treat and Extend or monthly regimens.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group I ranibizumab 0.5 mg monthly
    Arm description
    		 Ranibizumab 0.5 mg/0.05 mL (Monthly regimen)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    RFB002
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Ranibizumab 0.5 mg/0.05 mL (Monthly regimen)

    Arm title
    		 Group II ranibizumab 0.5 mg TER
    Arm description
    		 Ranibizumab 0.5 mg/0.05 mL (TER) treat and Extend regimen
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    RFB002
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Ranibizumab 0.5 mg/0.05 mL (TER) treat and Extend regimen

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The blinded roles were verified
    Number of subjects in period 1
    		Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Started
    323
    327
    Safety Set
    323
    326
    Completed
    290
    295
    Not completed
    33
    32
         Adverse event, serious fatal
    3
    4
         Consent withdrawn by subject
    14
    17
         Physician decision
    1
    3
         Adverse event, non-fatal
    9
    2
         Protocol deviation
    1
    2
         Lost to follow-up
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group I ranibizumab 0.5 mg monthly
    Reporting group description
    		 Ranibizumab 0.5 mg/0.05 mL (Monthly regimen)

    Reporting group title
    Group II ranibizumab 0.5 mg TER
    Reporting group description
    		 Ranibizumab 0.5 mg/0.05 mL (TER) treat and Extend regimen

    Reporting group values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER Total
    Number of subjects
    		 323 327 650
    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)
    		 42 36 78
        From 65-84 years
    		 234 249 483
        85 years and over
    		 47 42 89
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 75.3 ± 8.61 75.2 ± 8.13 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 179 181 360
        Male
    		 144 146 290

    End points

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    End points reporting groups
    Reporting group title
    Group I ranibizumab 0.5 mg monthly
    Reporting group description
    		 Ranibizumab 0.5 mg/0.05 mL (Monthly regimen)

    Reporting group title
    Group II ranibizumab 0.5 mg TER
    Reporting group description
    		 Ranibizumab 0.5 mg/0.05 mL (TER) treat and Extend regimen

    Primary: Change in best corrected visual acuity (BCVA) from Baseline to Month 12

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    End point title
    		 Change in best corrected visual acuity (BCVA) from Baseline to Month 12
    End point description
    Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement
    End point type
    Primary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    320
    323
    Units: Letters (EDTRS)
        least squares mean (standard error)
    6.2 ± 0.7
    8.1 ± 0.7
    Statistical analysis title
    		 Change in BCVA
    Comparison groups
    Group I ranibizumab 0.5 mg monthly v Group II ranibizumab 0.5 mg TER
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - The following hypothesis was tested at a one-sided 0.025 level. Non-inferiority with respect to BCVA: H01: μtreat and extend - μmonthly ≤ - Δ versus HA1: μtreat and extend - μmonthly > - Δ where μtreat and extend and μmonthly are the unknown mean changes from baseline in BCVA to Month 12 in the treat and extend regimen and the monthly regimen, respectively. Δ is the non-inferiority margin and is pre-defined to be 5 letters for the justification of the margin.

    Secondary: Number of visits scheduled

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    End point title
    		 Number of visits scheduled
    End point description
    The number of visits scheduled according to the treat and extend regimen after treatment initiation
    End point type
    Secondary
    End point timeframe
    From Month1 to Month 11
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    323
    327
    Units: Number of visits
        arithmetic mean (standard deviation)
    8.9 ± 2.56
    11.2 ± 2.37
    No statistical analyses for this end point

    Secondary: Change in BCVA from baseline to month 12

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    End point title
    		 Change in BCVA from baseline to month 12
    End point description
    Best Corrected Visual Acuity (BCVA) was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart at Baseline and Month 12 while participants were in a sitting position at a testing distance of 4 meters
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    320
    323
    Units: Letters (EDTRS)
        arithmetic mean (standard deviation)
    6.4 ± 14.11
    8 ± 11.61
    No statistical analyses for this end point

    Secondary: Average BCVA change from baseline to Month 12

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    End point title
    		 Average BCVA change from baseline to Month 12
    End point description
    Best Corrected Visual Acuity (BCVA) was assessed in a sitting position using ETDRS-like visual acuity testing charts at an initial testing distance of 4 meters. Mean Visual Acuity was averaged over all monthly assessments from Baseline to Month 12
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    320
    323
    Units: Letters (EDTRS)
        arithmetic mean (standard deviation)
    6.3 ± 10.5
    7.1 ± 9.41
    No statistical analyses for this end point

    Secondary: Mean change in visual acuity BCVA (letters) from Baseline to Month 12

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    End point title
    		 Mean change in visual acuity BCVA (letters) from Baseline to Month 12
    End point description
    Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) -like charts while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. For the mean change of best corrected visual acuity at Month 12 and compare to Baseline
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    323
    327
    Units: Letters (EDTRS)
    arithmetic mean (standard deviation)
        Month 1 (n=320, 322)
    4.6 ± 7.56
    4.2 ± 6.98
        Month 2 (n=240, 316)
    5.5 ± 8.64
    5.8 ± 8.58
        Month 3 (n=247, 311)
    6.7 ± 9.09
    6.7 ± 9.19
        Month 4 (n=213, 314)
    7 ± 10.9
    7.3 ± 9.95
        Month 5 (n=231, 302)
    6 ± 11.34
    7.7 ± 10.61
        month 6 (n=205, 302)
    6.9 ± 13.34
    7.9 ± 10.83
        Month 7 (n=230, 298)
    5.9 ± 14.25
    7.9 ± 11.36
        Month 8 (n=210, 295)
    7.5 ± 12.87
    7.9 ± 11.34
        Month 9 (n=179, 295)
    6.6 ± 13.63
    7.6 ± 12.56
        Month 10 (n=202, 296)
    6.3 ± 13.44
    7.6 ± 12.06
        Month 11 (n=180, 290)
    5.9 ± 14.12
    7.5 ± 12.48
        Month 12 (n=294, 295)
    6.6 ± 13.41
    7.9 ± 11.96
    No statistical analyses for this end point

    Secondary: Number of patients with a BCVA improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 letters from Baseline to Month 12

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    End point title
    		 Number of patients with a BCVA improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 letters from Baseline to Month 12
    End point description
    BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 letters of visual acuity at Month 12 as compared with baseline
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    323
    327
    Units: Number of participants
        Month 1,Gain of ≥ 1 letter (n=320,322)
    235
    233
        Month 1, Gain of ≥ 5 letters
    145
    145
        Month 1, Gain of ≥ 10 letters
    65
    58
        Month 1, Gain of ≥ 15 letters
    24
    23
        Month 1, Gain of ≥ 30 letters
    4
    2
        Month 2, Gain of >= 1 letter (n=226, 316)
    168
    244
        Month 2, Gain of >= 5 letters
    123
    184
        Month 2, Gain of >= 10 letters
    60
    88
        Month 2, Gain of >= 15 letters
    30
    39
        Month 2, Gain of >= 30 letters
    4
    3
        Month 3, Gain of >= 1 letter (n=161,311)
    120
    244
        Month 3, Gain of >= 5 letters
    98
    187
        Month 3, Gain of >= 10 letters
    57
    110
        Month 3, Gain of >= 15 letters
    28
    46
        Month 3, Gain of >= 30 letters
    2
    3
        Month 4, Gain of >= 1 letter (n=128, 314)
    96
    249
        Month 4, Gain of >= 5 letters
    67
    198
        Month 4, Gain of >=10 letters
    48
    118
        Month 4, Gain of >= 15 letters
    25
    60
        Month 4, Gain of >= 30 letters
    4
    8
        Month 5, Gain of >= 1 letter (n=114, 302)
    84
    243
        Month 5, Gain of >= 5 letters
    64
    197
        Month 5, Gain of >= 10 letters
    42
    116
        Month 5, Gain of >= 15 letters
    19
    59
        Month 5, Gain of >= 30 letters
    3
    10
        Month 6, Gain of >= 1 letter (n=117, 302)
    85
    238
        Month 6, Gain of >= 5 letters
    68
    197
        Month 6, Gain of >= 10 letters
    42
    125
        Month 6, Gain of >= 15 letters
    19
    61
        Month 6, Gain of >= 30 letters
    2
    11
        Month 7, Gain of >= 1 letter (n=176, 298)
    126
    235
        Month 7, Gain of >= 5 letters
    94
    196
        Month 7, Gain of >= 10 letters
    57
    123
        Month 7, Gain of >= 15 letters
    33
    69
        Month 7, Gain of >= 30 letters
    7
    9
        Month 8, Gain of >= 1 letter (n=163, 295)
    124
    228
        Month 8, Gain of >= 5 letters
    108
    198
        Month 8, Gain of >= 10 letters
    69
    130
        Month 8, Gain of >= 15 letters
    40
    72
        Month 8, Gain of >= 30 letters
    4
    9
        Month 9, Gain of >= 1 letter (n=129, 295)
    93
    229
        Month 9, Gain of >= 5 letters
    78
    186
        Month 9, Gain of >= 10 letters
    52
    128
        Month 9, Gain of >= 15 letters
    28
    70
        Month 9, Gain of >= 30 letters
    5
    8
        Month 10, Gain of >= 1 letter (n=159, 296)
    113
    230
        Month 10, Gain of >= 5 letters
    98
    190
        Month 10, Gain of >= 10 letters
    60
    126
        Month 10, Gain of >= 15 letters
    32
    74
        Month 10, Gain of >= 30 letters
    4
    10
        Month 11, Gain of >= 1 letter (131, 290)
    94
    222
        Month 11, Gain of >= 5 letters
    79
    187
        Month 11, Gain of >= 10 letters
    51
    130
        Month 11, Gain of >= 15 letters
    32
    74
        Month 11, Gain of >= 30 letters
    5
    9
        Month 12, Gain of >= 1 letter (n=291, 295)
    217
    226
        Month 12, Gain of >= 5 letters
    178
    199
        Month 12, Gain of >= 10 letters
    123
    135
        Month 12, Gain of >= 15 letters
    75
    77
        Month 12, Gain of >= 30 letters
    12
    8
    No statistical analyses for this end point

    Secondary: Number of patients with Best Corrected Visual Acuity (BCVA) loss <5, <10, and <15 letters by visit

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    End point title
    		 Number of patients with Best Corrected Visual Acuity (BCVA) loss <5, <10, and <15 letters by visit
    End point description
    Best Corrected Visual Acuity (BCVA) was assessed in a sitting position using ETDRS-like visual acuity testing charts at an initial testing distance of 4 meters.Best Corrected Visual Acuity (BCVA) was assessed in a sitting position using ETDRS-like visual acuity testing charts at an initial testing distance of 4 meters.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    323
    327
    Units: Number of participants
        Month 1, Loss of < 5 letters (n=320, 322)
    296
    295
        Month 1, Loss of < 10 letters
    313
    314
        Month 1, Loss of < 15 letters
    319
    320
        Month 2, Loss of < 5 letters (n=226, 316)
    205
    288
        Month 2, Loss of < 10 letters
    220
    306
        Month 2, Loss of < 15 letters
    223
    309
        Month 3, Loss of < 5 letters (n=161, 311)
    146
    289
        Month 3, Loss of < 10 letters
    158
    299
        Month 3, Loss of < 15 letters
    160
    304
        Month 4, Loss of < 5 letters (n=128, 314)
    114
    286
        Month 4, Loss of < 10 letters
    128
    301
        Month 4, Loss of < 15 letters
    124
    307
        Month 5, Loss of < 5 letters (n=114, 302)
    97
    276
        Month 5, Loss of < 10 letters
    105
    287
        Month 5, Loss of < 15 letters
    108
    295
        Month 6, Loss of < 5 letters (n=117, 302)
    104
    271
        Month 6, Loss of < 10 letters
    110
    286
        Month 6, Loss of < 15 letters
    111
    298
        Month 7, Loss of < 5 letters (n=176, 298)
    148
    268
        Month 7, Loss of < 10 letters
    162
    279
        Month 7, Loss of < 15 letters
    166
    289
        Month 8, Loss of < 5 letters (n=163, 295)
    145
    262
        Month 8, Loss of < 10 letters
    155
    276
        Month 8, Loss of < 15 letters
    155
    286
        Month 9, Loss of < 5 letters (n=129, 295)
    110
    258
        Month 9, Loss of < 10 letters
    120
    270
        Month 9, Loss of < 15 letters
    122
    281
        Month 10, Loss of < 5 letters(n=159, 296)
    133
    253
        Month 10, Loss of < 10 letters
    147
    276
        Month 10, Loss of < 15 letters
    150
    285
        Month 11, Loss of < 5 letters (n=131, 290)
    105
    251
        Month 11, Loss of < 10 letters
    118
    263
        Month 11, Loss of < 15 letters
    121
    275
        Month 12, Loss of < 5 letters (291, 295)
    247
    256
        Month 12, Loss of < 10 letters
    267
    272
        Month 12, Loss of < 15 letters
    273
    284
    No statistical analyses for this end point

    Secondary: Number of patients with a BCVA value of ≥ 73 letters (approximate 20/40 Snellen chart equivalent) at Month 12

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    End point title
    		 Number of patients with a BCVA value of ≥ 73 letters (approximate 20/40 Snellen chart equivalent) at Month 12
    End point description
    Best Corrected Visual Acuity (BCVA) was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at baseline and month 12 while participants were in a sitting position at a testing distance of 4 meters. The range of EDTRS is 0 to 100 letters. BCVA above 73 letters at Month 12 indicates a positive outcome
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    323
    327
    Units: Number of participants
        Month 1 (n=320, 322)
    106
    106
        Month 2 (n=226, 316)
    74
    136
        Month 3 (n=161, 311)
    67
    148
        Month 4 (n=128, 314)
    60
    147
        Month 5 (n=114, 302)
    51
    156
        Month 6 (n=117, 302)
    58
    155
        Month 7 (n=176, 298)
    78
    150
        Month 8 (n=163, 295)
    84
    155
        Month 9 (n=129, 295)
    68
    156
        Month 10 (n=159, 296)
    74
    149
        Month 11 (n=131, 290
    63
    143
        Month 12 (n=291, 295)
    131
    149
    No statistical analyses for this end point

    Secondary: The mean number of treatment frequency

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    End point title
    		 The mean number of treatment frequency
    End point description
    The number of injections received
    End point type
    Secondary
    End point timeframe
    12 Months
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    323
    327
    Units: Number of injections
        arithmetic mean (standard deviation)
    8.7 ± 2.68
    11 ± 2.5
    No statistical analyses for this end point

    Secondary: The average number of days between injections

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    End point title
    		 The average number of days between injections
    End point description
    The average dosing interval was measured as the average number of days between injections
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    323
    327
    Units: days
        arithmetic mean (standard deviation)
    40.3 ± 11.28
    29.4 ± 3.27
    No statistical analyses for this end point

    Secondary: Percentage of participants with fluid free macula over time up to Month 12

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    End point title
    		 Percentage of participants with fluid free macula over time up to Month 12
    End point description
    OCT (optical coherence tomography) was used to assess intra-retinal fluid as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography). Fluid free macula refers to absence of macular edema (as assessed by the reading center). The full analysis set was used for this evaluation but the count presented are the counts of patients in the specific treatment group who have a value for the macular edema (center involvement) at study completion. These total counts are used as the denominator for the percentages
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    291
    290
    Units: Percentage of participants
    number (not applicable)
        Absent
    60.5
    60.7
        Definite
    39.5
    39
        Can't grade
    0
    0.3
    No statistical analyses for this end point

    Secondary: Change in central subfield retinal thickness (CSFT) over time

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    End point title
    		 Change in central subfield retinal thickness (CSFT) over time
    End point description
    OCT (optical coherence tomography) was used to assess CSFT (Central Sub-Field Thickness) representing the average retinal thickness of the circular area within 1 mm diameter around the foveal center. The Ns in the rows is the number of patients with a value for both baseline and the specific post-baseline visit
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    323
    327
    Units: microns
    arithmetic mean (standard deviation)
        Month 1 (n=311, 316)
    -137.6 ± 132.33
    -126.8 ± 119.47
        Month 2 (n=220, 311)
    -151.6 ± 151.15
    -149.2 ± 137.6
        Month 3 (n=157, 304)
    -149.8 ± 167.26
    -151.8 ± 149.51
        Month 4 (n=125, 307)
    -141.8 ± 183.71
    -161.3 ± 149.36
        Month 5 (n=110, 295)
    -138.6 ± 160.04
    -160.9 ± 148.23
        Month 6 (n=113, 298)
    -140.1 ± 156.25
    -163.4 ± 157.18
        Month 7 (n=173, 296)
    -146.6 ± 160.72
    -166.9 ± 161.49
        Month 8 (n=159, 290)
    -153.4 ± 151.93
    -170.4 ± 156.68
        Month 9 (n=126, 286)
    -150.2 ± 153.82
    -169.3 ± 156.5
        Month 10 (n=156, 291)
    -154.6 ± 162.77
    -170.9 ± 153.9
        Month 11 (n=127, 285)
    -133.1 ± 170.47
    -174.8 ± 163.16
        Month 12 (n=289, 287)
    -172.1 ± 162.81
    -173.3 ± 154.13
    No statistical analyses for this end point

    Secondary: Percentage of patients with Choroidal Neovascularization (CNV) leakage assessed by fluorescein angiography (FA) in the study eye at

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    End point title
    		 Percentage of patients with Choroidal Neovascularization (CNV) leakage assessed by fluorescein angiography (FA) in the study eye at
    End point description
    To evaluate presence of active CNV leakage on fluorescein angiography (FA) by reading center over time up to Month 12. The full analysis set was used for this evaluation but the count presented are the counts of patients in the specific treatment group who have a value for the presence of leakage at study completion. These total counts are used as the denominator for the percentages.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    278
    286
    Units: Percentage of participants
    number (not applicable)
        Yes
    18.7
    17.1
        No
    74.1
    76.9
        Can't grade
    0
    2.4
        Not applicable
    7.2
    3.5
    No statistical analyses for this end point

    Secondary: Change from Baseline in composite score of the National Eye Institute-Visual Function Questionnaire-25 (NEI-VFQ-25)

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    End point title
    		 Change from Baseline in composite score of the National Eye Institute-Visual Function Questionnaire-25 (NEI-VFQ-25)
    End point description
    The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicates the best possible response. The composite score and score of each of each construct also ranged from 0 to 100 as they are calculated as total scores divided by the number of questions. The higher the values of total scores represent better outcome
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Group I ranibizumab 0.5 mg monthly Group II ranibizumab 0.5 mg TER
    Number of subjects analysed
    290
    293
    Units: Score on a scale
        arithmetic mean (standard deviation)
    2.3 ± 13.93
    4 ± 13.72
    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
    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
    18.1
    Reporting groups
    Reporting group title
    Ranibizumab 0.5 mg Treat and Extend
    Reporting group description
    		 Ranibizumab 0.5 mg Treat and Extend

    Reporting group title
    Ranibizumab 0.5 mg Monthly
    Reporting group description
    		 Ranibizumab 0.5 mg Monthly

    Serious adverse events
    		 Ranibizumab 0.5 mg Treat and Extend Ranibizumab 0.5 mg Monthly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 323 (12.07%)
    42 / 326 (12.88%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 323 (0.00%)
    2 / 326 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 323 (0.62%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 323 (0.62%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 323 (0.62%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood pressure decreased
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intraocular pressure increased (Fellow eye)
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraocular pressure increased (Study eye)
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 323 (0.62%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 323 (0.62%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery thrombosis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 323 (0.00%)
    2 / 326 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 323 (0.00%)
    2 / 326 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 323 (0.93%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIth nerve paresis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 323 (0.62%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract (Fellow eye)
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal erosion (Study eye)
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal infiltrates (Study eye)
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryostenosis acquired (Fellow eye)
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryostenosis acquired (Study eye)
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular hole (Study eye)
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment (Study eye)
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal haemorrhage (Study eye)
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear (Study eye)
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage (Study eye)
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder prolapse
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 323 (0.62%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis (Fellow eye)
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis (Study eye)
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 323 (1.24%)
    2 / 326 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercreatininaemia
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 326 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Ranibizumab 0.5 mg Treat and Extend Ranibizumab 0.5 mg Monthly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    133 / 323 (41.18%)
    141 / 326 (43.25%)
    Investigations
    Intraocular pressure increased (Fellow eye)
         subjects affected / exposed
    3 / 323 (0.93%)
    8 / 326 (2.45%)
         occurrences all number
    3
    13
    Intraocular pressure increased (Study eye)
         subjects affected / exposed
    27 / 323 (8.36%)
    28 / 326 (8.59%)
         occurrences all number
    48
    63
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 323 (7.12%)
    13 / 326 (3.99%)
         occurrences all number
    24
    14
    Eye disorders
    Age-related macular degeneration (Fellow eye)
         subjects affected / exposed
    9 / 323 (2.79%)
    4 / 326 (1.23%)
         occurrences all number
    9
    4
    Blepharitis (Fellow eye)
         subjects affected / exposed
    6 / 323 (1.86%)
    8 / 326 (2.45%)
         occurrences all number
    6
    10
    Cataract (Fellow eye)
         subjects affected / exposed
    7 / 323 (2.17%)
    10 / 326 (3.07%)
         occurrences all number
    7
    10
    Cataract (Study eye)
         subjects affected / exposed
    7 / 323 (2.17%)
    7 / 326 (2.15%)
         occurrences all number
    7
    8
    Choroidal neovascularisation (Fellow eye)
         subjects affected / exposed
    6 / 323 (1.86%)
    7 / 326 (2.15%)
         occurrences all number
    7
    7
    Conjunctival haemorrhage (Study eye)
         subjects affected / exposed
    14 / 323 (4.33%)
    19 / 326 (5.83%)
         occurrences all number
    15
    23
    Dry eye (Fellow eye)
         subjects affected / exposed
    7 / 323 (2.17%)
    6 / 326 (1.84%)
         occurrences all number
    7
    6
    Dry eye (Study eye)
         subjects affected / exposed
    6 / 323 (1.86%)
    7 / 326 (2.15%)
         occurrences all number
    6
    7
    Eye pain (Study eye)
         subjects affected / exposed
    10 / 323 (3.10%)
    5 / 326 (1.53%)
         occurrences all number
    11
    7
    Neovascular age-related macular degeneration (Fellow eye)
         subjects affected / exposed
    8 / 323 (2.48%)
    16 / 326 (4.91%)
         occurrences all number
    8
    20
    Retinal haemorrhage (Study eye)
         subjects affected / exposed
    5 / 323 (1.55%)
    8 / 326 (2.45%)
         occurrences all number
    5
    8
    Visual acuity reduced (Study eye)
         subjects affected / exposed
    15 / 323 (4.64%)
    12 / 326 (3.68%)
         occurrences all number
    16
    15
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 323 (1.86%)
    12 / 326 (3.68%)
         occurrences all number
    8
    12
    Conjunctivitis (Study eye)
         subjects affected / exposed
    10 / 323 (3.10%)
    6 / 326 (1.84%)
         occurrences all number
    10
    6
    Influenza
         subjects affected / exposed
    9 / 323 (2.79%)
    12 / 326 (3.68%)
         occurrences all number
    9
    13
    Nasopharyngitis
         subjects affected / exposed
    18 / 323 (5.57%)
    26 / 326 (7.98%)
         occurrences all number
    19
    32

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2015
    Clarification for the specific timing of the study completion visit in the Treat and Extend regimen (TER) was added. Clarification on the timing of SAE reporting for patients has been added. Minor editorial clarifications were added as well.

    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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