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    Clinical Trial Results:
    A phase 3 randomized, double-masked, controlled trial to establish the safety and efficacy of intravitreous administration of Fovista™ (Anti PDGF-B pegylated aptamer) administered in combination with either Avastin® or Eylea® compared to Avastin® or Eylea® monotherapy in subjects with subfoveal neovascular age-related macular degeneration

    Summary
    EudraCT number
    		 2013-003018-42
    Trial protocol
    		 PT   ES   FI   NO   DE   EE   LV   SK   IT   AT   HU   HR   CZ  
    Global end of trial date
    15 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2019
    First version publication date
    18 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OPH1004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01940887
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ophthotech Corporation
    Sponsor organisation address
    One Penn Plaza, Suite 3520 , New York, United States, NY 10119
    Public contact
    Fang Li, Ophthotech Corporation, +1 212-845-8219, fang.li@ophthotech.com
    Scientific contact
    Fang Li, Ophthotech Corporation, +1 212-845-8219, fang.li@ophthotech.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
    15 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objectives of this study are to evaluate the safety and efficacy of Fovista (E10030) intravitreous administration when administered in combination with either Avastin or Eylea compared to Avastin or Eylea monotherapy in subjects with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD).
    Protection of trial subjects
    All subjects signed the informed consent before undergoing any study-related procedure. An independent data monitoring committee reviewed subject safety data during the course of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Portugal: 21
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    Croatia: 44
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Czech Republic: 29
    Country: Number of subjects enrolled
    Estonia: 16
    Country: Number of subjects enrolled
    France: 49
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 98
    Country: Number of subjects enrolled
    Italy: 57
    Country: Number of subjects enrolled
    Latvia: 15
    Country: Number of subjects enrolled
    Israel: 60
    Country: Number of subjects enrolled
    Colombia: 12
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Argentina: 7
    Country: Number of subjects enrolled
    United States: 189
    Worldwide total number of subjects
    645
    EEA total number of subjects
    363
    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)
    56
    From 65 to 84 years
    480
    85 years and over
    109

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 214 centers (107 in North America and 107 in the rest of the world) in 22 countries (20 of which enrolled patients) between 19 May 2014 and 15 September 2017. Written informed consent was obtained before any of the Screening details listed below were performed.

    Pre-assignment
    Screening details
    		 Medical&ophthalmologic history,protocol refraction&visual acuity,ophthalmologic examination,Goldmann Applanation Tonometry,vital signs,physical examination, performance status,ECG,color fundus photographs,Fluorescein Angiograms,Optical Coherence Tomography,laboratory&pregnancy tests&concomitant medication were assessed at screening prior to Day1

    Period 1
    Period 1 title
    Year 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    It was the responsibility of the Principal Investigator to ensure that the physician assessing AEs, the VA examiner, all masked study personnel, and the subject remained masked to the subject’s treatment assignment of Fovista or Sham.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fovista + Avastin or Eylea
    Arm description
    		 Fovista 1.5 mg/eye + Avastin 1.25 mg/eye or Eylea 2 mg/eye. Within this treatment group, subjects were randomized in a 1:1 ratio to either Avastin 1.25 mg/eye or Eylea 2 mg/eye. NOTE: 1 subject who was randomized but did not receive study drug is excluded from the number of subjects starting this period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fovista
    Investigational medicinal product code
    Other name
    E10030, pegpleranib
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Avastin or Eylea was administered first, and Fovista injection was administered second. Subjects randomized to receive Avastin were treated with Fovista in combination with Avastin monthly for 24 months. Subjects randomized to receive Eylea were treated with Fovista in combination with Eylea every month for the first 3 doses (Day 1, Month 1, and Month 2) and every other month thereafter (ie, Months 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22).

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Avastin or Eylea was administered first, and Fovista injection was administered second. Subjects randomized to receive Avastin were treated with Fovista in combination with Avastin monthly for 24 months. Subjects randomized to receive Eylea were treated with Fovista in combination with Eylea every month for the first 3 doses (Day 1, Month 1, and Month 2) and every other month thereafter (ie, Months 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22).

    Investigational medicinal product name
    Eylea
    Investigational medicinal product code
    Other name
    Aflibercept
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Avastin or Eylea was administered first, and Fovista injection was administered second. Subjects randomized to receive Avastin were treated with Fovista in combination with Avastin monthly for 24 months. Subjects randomized to receive Eylea were treated with Fovista in combination with Eylea every month for the first 3 doses (Day 1, Month 1, and Month 2) and every other month thereafter (ie, Months 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22).

    Arm title
    		 Fovista Sham + Avastin or Eylea
    Arm description
    		 Fovista Sham + Avastin 1.25 mg/eye or Eylea 2 mg/eye. Within this treatment group, subjects were randomized in a 1:1 ratio to either Avastin 1.25 mg/eye or Eylea 2 mg/eye. NOTE: 2 subjects who were randomized but did not receive study drug are excluded from the number of subjects starting this period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Avastin or Eylea was administered first, and Fovista Sham injection was administered second. Subjects randomized to receive Avastin were treated with Fovista Sham in combination with Avastin monthly for 24 months. Subjects randomized to receive Eylea were treated with Fovista Sham in combination with Eylea every month for the first 3 doses (Day 1, Month 1, and Month 2) and every other month thereafter (ie, Months 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22).

    Investigational medicinal product name
    Eylea
    Investigational medicinal product code
    Other name
    Aflibercept
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Avastin or Eylea was administered first, and Fovista Sham injection was administered second. Subjects randomized to receive Avastin were treated with Fovista Sham in combination with Avastin monthly for 24 months. Subjects randomized to receive Eylea were treated with Fovista Sham in combination with Eylea every month for the first 3 doses (Day 1, Month 1, and Month 2) and every other month thereafter (ie, Months 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22).

    Number of subjects in period 1 [1]
    		Fovista + Avastin or Eylea Fovista Sham + Avastin or Eylea
    Started
    322
    320
    Completed
    283
    297
    Not completed
    39
    23
         Adverse event, serious fatal
    6
    3
         Physician decision
    7
    3
         Consent withdrawn by subject
    18
    9
         Adverse event, non-fatal
    6
    6
         Lost to follow-up
    2
    1
         Protocol deviation
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Three (3) patients who were enrolled and randomized to treatment did not receive any treatment. These patients are not included in Year 1 period. Therefore, there are 3 patients fewer in the Year 1 period compared to the worldwide number enrolled.
    Period 2
    Period 2 title
    Year 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    It was the responsibility of the Principal Investigator to ensure that the physician assessing AEs, the VA examiner, all masked study personnel, and the subject remained masked to the subject’s treatment assignment of Fovista or Sham.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fovista + Avastin or Eylea
    Arm description
    		 Fovista 1.5 mg/eye + Avastin 1.25 mg/eye or Eylea 2 mg/eye. Within this treatment group, subjects were randomized in a 1:1 ratio to either Avastin 1.25 mg/eye or Eylea 2 mg/eye.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fovista
    Investigational medicinal product code
    Other name
    E10030, pegpleranib
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Avastin or Eylea was administered first, and Fovista injection was administered second. Subjects randomized to receive Avastin were treated with Fovista in combination with Avastin monthly for 24 months. Subjects randomized to receive Eylea were treated with Fovista in combination with Eylea every month for the first 3 doses (Day 1, Month 1, and Month 2) and every other month thereafter (ie, Months 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22).

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Avastin or Eylea was administered first, and Fovista injection was administered second. Subjects randomized to receive Avastin were treated with Fovista in combination with Avastin monthly for 24 months. Subjects randomized to receive Eylea were treated with Fovista in combination with Eylea every month for the first 3 doses (Day 1, Month 1, and Month 2) and every other month thereafter (ie, Months 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22).

    Investigational medicinal product name
    Eylea
    Investigational medicinal product code
    Other name
    Aflibercept
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Avastin or Eylea was administered first, and Fovista injection was administered second. Subjects randomized to receive Avastin were treated with Fovista in combination with Avastin monthly for 24 months. Subjects randomized to receive Eylea were treated with Fovista in combination with Eylea every month for the first 3 doses (Day 1, Month 1, and Month 2) and every other month thereafter (ie, Months 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22).

    Arm title
    		 Fovista Sham + Avastin or Eylea
    Arm description
    		 Fovista Sham + Avastin 1.25 mg/eye or Eylea 2 mg/eye Within this treatment group, subjects were randomized in a 1:1 ratio to either Avastin 1.25 mg/eye or Eylea 2 mg/eye.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Avastin or Eylea was administered first, and Fovista Sham injection was administered second. Subjects randomized to receive Avastin were to be treated with Fovista Sham in combination with Avastin monthly for 24 months. Subjects randomized to receive Eylea were to be treated with Fovista Sham in combination with Eylea every month for the first 3 doses (Day 1, Month 1, and Month 2) and every other month thereafter (ie, Months 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22).

    Investigational medicinal product name
    Eylea
    Investigational medicinal product code
    Other name
    Aflibercept
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Avastin or Eylea was administered first, and Fovista Sham injection was administered second. Subjects randomized to receive Avastin were to be treated with Fovista Sham in combination with Avastin monthly for 24 months. Subjects randomized to receive Eylea were to be treated with Fovista Sham in combination with Eylea every month for the first 3 doses (Day 1, Month 1, and Month 2) and every other month thereafter (ie, Months 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22).

    Number of subjects in period 2
    		Fovista + Avastin or Eylea Fovista Sham + Avastin or Eylea
    Started
    283
    297
    Completed
    66
    75
    Not completed
    217
    222
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    8
    8
         Physician decision
    8
    1
         Adverse event, non-fatal
    8
    2
         Lost to follow-up
    1
    6
         Sponsor decision, early termination of study
    192
    203

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fovista + Avastin or Eylea
    Reporting group description
    		 Fovista 1.5 mg/eye + Avastin 1.25 mg/eye or Eylea 2 mg/eye. Within this treatment group, subjects were randomized in a 1:1 ratio to either Avastin 1.25 mg/eye or Eylea 2 mg/eye. NOTE: 1 subject who was randomized but did not receive study drug is excluded from the number of subjects starting this period.

    Reporting group title
    Fovista Sham + Avastin or Eylea
    Reporting group description
    		 Fovista Sham + Avastin 1.25 mg/eye or Eylea 2 mg/eye. Within this treatment group, subjects were randomized in a 1:1 ratio to either Avastin 1.25 mg/eye or Eylea 2 mg/eye. NOTE: 2 subjects who were randomized but did not receive study drug are excluded from the number of subjects starting this period.

    Reporting group values
    		 Fovista + Avastin or Eylea Fovista Sham + Avastin or Eylea Total
    Number of subjects
    		 322 320 642
    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)
    		 31 25 56
        From 65-84 years
    		 239 239 478
        85 years and over
    		 52 56 108
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 76.5 ± 8.36 76.6 ± 8.36 -
    Gender categorical
    Units: Subjects
        Female
    		 178 192 370
        Male
    		 144 128 272
    Subject analysis sets

    Subject analysis set title
    Fovista + Avastin or Eylea, ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects in the Fovista + Avastin or Fovista + Eylea arm who received at least one dose of study drug, irrespective of the dose actually received. Subjects were analyzed in the dose group assigned at randomization.

    Subject analysis set title
    Fovista Sham + Avastin or Eylea, ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects in the Fovista Sham + Avastin or Fovista Sham + Eylea arm who received at least one dose of study drug, irrespective of the dose received. Subjects were analyzed in the dose group assigned at randomization.

    Subject analysis sets values
    		 Fovista + Avastin or Eylea, ITT Fovista Sham + Avastin or Eylea, ITT
    Number of subjects
    322
    320
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    31
    25
        From 65-84 years
    269
    239
        85 years and over
    52
    56
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    76.5 ± 8.36
    76.6 ± 8.36
    Gender categorical
    Units: Subjects
        Female
    178
    192
        Male
    144
    128

    End points

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    End points reporting groups
    Reporting group title
    Fovista + Avastin or Eylea
    Reporting group description
    		 Fovista 1.5 mg/eye + Avastin 1.25 mg/eye or Eylea 2 mg/eye. Within this treatment group, subjects were randomized in a 1:1 ratio to either Avastin 1.25 mg/eye or Eylea 2 mg/eye. NOTE: 1 subject who was randomized but did not receive study drug is excluded from the number of subjects starting this period.

    Reporting group title
    Fovista Sham + Avastin or Eylea
    Reporting group description
    		 Fovista Sham + Avastin 1.25 mg/eye or Eylea 2 mg/eye. Within this treatment group, subjects were randomized in a 1:1 ratio to either Avastin 1.25 mg/eye or Eylea 2 mg/eye. NOTE: 2 subjects who were randomized but did not receive study drug are excluded from the number of subjects starting this period.
    Reporting group title
    Fovista + Avastin or Eylea
    Reporting group description
    		 Fovista 1.5 mg/eye + Avastin 1.25 mg/eye or Eylea 2 mg/eye. Within this treatment group, subjects were randomized in a 1:1 ratio to either Avastin 1.25 mg/eye or Eylea 2 mg/eye.

    Reporting group title
    Fovista Sham + Avastin or Eylea
    Reporting group description
    		 Fovista Sham + Avastin 1.25 mg/eye or Eylea 2 mg/eye Within this treatment group, subjects were randomized in a 1:1 ratio to either Avastin 1.25 mg/eye or Eylea 2 mg/eye.

    Subject analysis set title
    Fovista + Avastin or Eylea, ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects in the Fovista + Avastin or Fovista + Eylea arm who received at least one dose of study drug, irrespective of the dose actually received. Subjects were analyzed in the dose group assigned at randomization.

    Subject analysis set title
    Fovista Sham + Avastin or Eylea, ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects in the Fovista Sham + Avastin or Fovista Sham + Eylea arm who received at least one dose of study drug, irrespective of the dose received. Subjects were analyzed in the dose group assigned at randomization.

    Primary: Mean Change in Visual Acuity (ETDRS Letters) from Baseline to Month 12

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    End point title
    		 Mean Change in Visual Acuity (ETDRS Letters) from Baseline to Month 12
    End point description
    The primary efficacy endpoint was the mean change in VA (ETDRS letters) from Baseline to Month 12. All VA assessments were performed by the study refractionist/ophthalmologist. Comparison of the mean change in VA in ETDRS letters between the two groups was made using analysis of covariance with baseline VA as a covariate, stratified by lesion subtype. VA was assessed on the ITT population which consisted of all randomized subjects who received at least one dose of study drug, irrespective of the dose actually received. Subjects were analyzed as per the dose group assigned at randomization. Subjects were included in a particular analysis, for a particular population, if relevant data were available for analysis (e.g., the primary analysis required one baseline and at least one post baseline VA measurement, to calculate a change score).
    End point type
    Primary
    End point timeframe
    From Baseline to Month 12
    End point values
    		 Fovista + Avastin or Eylea, ITT Fovista Sham + Avastin or Eylea, ITT
    Number of subjects analysed
    322
    320
    Units: Visual Acuity (ETDRS letters)
        least squares mean (standard error)
    9.42 ± 0.85
    9.04 ± 0.85
    Statistical analysis title
    		 Model for Repeated Measures
    Statistical analysis description
    The model was fitted by using restricted maximum likelihood (REML). The model included the indicator of treatment with Avastin or Eylea, and the cross-classification of baseline VA (≥ 47 letters vs. < 47 letters) and lesion subtype (> 50% classic vs. ≤ 50% classic) as used in the randomization as covariates. Fixed effects included treatment, visit, and treatment*visit. The level of significance (α) was set at 5% (two-tailed).
    Comparison groups
    Fovista + Avastin or Eylea, ITT v Fovista Sham + Avastin or Eylea, ITT
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7382
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.86
         upper limit
    		 2.62

    Secondary: Gain of 20 or More ETDRS Letters from Baseline to Month 12

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    End point title
    		 Gain of 20 or More ETDRS Letters from Baseline to Month 12
    End point description
    A secondary endpoint was to assess the proportion of subjects gaining ≥ 20 ETDRS letters from Baseline to Month 12. All VA assessments were performed by the study refractionist/ophthalmologist. VA was assessed on the ITT population which consisted of all randomized subjects who received at least one dose of study drug, irrespective of the dose actually received. Subjects were analyzed as per the dose group assigned at randomization. Subjects were included in a particular analysis, for a particular population, if relevant data were available for analysis (e.g., the primary analysis required one baseline and at least one post baseline VA measurement, to calculate a change score).
    End point type
    Secondary
    End point timeframe
    From Baseline to Month 12
    End point values
    		 Fovista + Avastin or Eylea, ITT Fovista Sham + Avastin or Eylea, ITT
    Number of subjects analysed
    322
    320
    Units: Percentage of subjects
    number (not applicable)
        Yes
    23.3
    22.2
        No
    62.7
    70.6
        Missing
    14.0
    7.2
    No statistical analyses for this end point

    Secondary: Loss of 5 or More ETDRS Letters from Baseline to Month 12

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    End point title
    		 Loss of 5 or More ETDRS Letters from Baseline to Month 12
    End point description
    A secondary endpoint was to assess the proportion of subjects losing ≥ 5 ETDRS letters from Baseline to Month 12. All VA assessments were performed by the study refractionist/ophthalmologist. VA was assessed on the ITT population which consisted of all randomized subjects who received at least one dose of study drug, irrespective of the dose actually received. Subjects were analyzed as per the dose group assigned at randomization. Subjects were included in a particular analysis, for a particular population, if relevant data were available for analysis (e.g., the primary analysis required one baseline and at least one post baseline VA measurement, to calculate a change score).
    End point type
    Secondary
    End point timeframe
    From Baseline to Month 12
    End point values
    		 Fovista + Avastin or Eylea, ITT Fovista Sham + Avastin or Eylea, ITT
    Number of subjects analysed
    322
    320
    Units: Percentage of subjects
    number (not applicable)
        Yes
    12.4
    13.4
        No
    73.6
    79.4
        Missing
    14.0
    7.2
    No statistical analyses for this end point

    Secondary: VA (ETDRS Snellen Equivalent) of 20/25 or Better at Month 12

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    End point title
    		 VA (ETDRS Snellen Equivalent) of 20/25 or Better at Month 12
    End point description
    A secondary endpoint was to assess the proportion of subjects in each treatment group achieving VA of 20/25 or better at Month 12. All VA assessments were performed by the study refractionist/ophthalmologist. VA was assessed on the ITT population which consisted of all randomized subjects who received at least one dose of study drug, irrespective of the dose actually received. Subjects were analyzed as per the dose group assigned at randomization. Subjects were included in a particular analysis, for a particular population, if relevant data were available for analysis (e.g., the primary analysis required one baseline and at least one post baseline VA measurement, to calculate a change score).
    End point type
    Secondary
    End point timeframe
    From Baseline to Month 12
    End point values
    		 Fovista + Avastin or Eylea, ITT Fovista Sham + Avastin or Eylea, ITT
    Number of subjects analysed
    322
    320
    Units: Percentage of subjects
    number (not applicable)
        Yes
    13.7
    18.1
        No
    72.4
    74.7
        Missing
    14.0
    7.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded starting after the first dose of the trial drug and continuing until end of study.
    Adverse event reporting additional description
    AEs were reported for the safety population (all subjects who received 1+ doses of study drug [Fovista, Avastin, Eylea or Sham]). Subjects who had ever received an injection of Fovista were analyzed in the Fovista+Avastin/Eylea group. Causally related occurrences included events reported as related to injection procedure or related to study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Fovista + Avastin or Eylea, year 1
    Reporting group description
    		 Fovista 1.5 mg/eye + Avastin 1.25 mg/eye or Eylea 2 mg/eye (all subjects received at least one dose of study drug)

    Reporting group title
    Fovista Sham + Avastin or Eylea, year 1
    Reporting group description
    		 Fovista Sham + Avastin 1.25 mg/eye or Eylea 2 mg/eye (all subjects received at least one dose of study drug)

    Serious adverse events
    		 Fovista + Avastin or Eylea, year 1 Fovista Sham + Avastin or Eylea, year 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    58 / 322 (18.01%)
    32 / 320 (10.00%)
         number of deaths (all causes)
    7
    4
         number of deaths resulting from adverse events
    7
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer stage I
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colon cancer recurrent
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer stage IV
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal papilloma of breast
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (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
    1 / 322 (0.31%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma recurrent
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Femoral artery occlusion
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 322 (0.62%)
    3 / 320 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (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
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 322 (0.62%)
    3 / 320 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (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
    Cerebral haematoma
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Autoimmune uveitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal endotheliitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric dysplasia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 322 (0.00%)
    2 / 320 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland mass
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (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
    Calculus bladder
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (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
    2 / 322 (0.62%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 322 (0.31%)
    2 / 320 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    4 / 322 (1.24%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nosocomial infection
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 322 (1.55%)
    2 / 320 (0.63%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fovista + Avastin or Eylea, year 1 Fovista Sham + Avastin or Eylea, year 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    222 / 322 (68.94%)
    212 / 320 (66.25%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    22 / 322 (6.83%)
    20 / 320 (6.25%)
         occurrences all number
    46
    35
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    39 / 322 (12.11%)
    31 / 320 (9.69%)
         occurrences all number
    85
    48
    Punctate keratitis
         subjects affected / exposed
    21 / 322 (6.52%)
    14 / 320 (4.38%)
         occurrences all number
    34
    39
    Eye pain
         subjects affected / exposed
    18 / 322 (5.59%)
    21 / 320 (6.56%)
         occurrences all number
    26
    35
    Vitreous detachment
         subjects affected / exposed
    20 / 322 (6.21%)
    19 / 320 (5.94%)
         occurrences all number
    21
    23
    Neovascular age-related macular degeneration
         subjects affected / exposed
    16 / 322 (4.97%)
    19 / 320 (5.94%)
         occurrences all number
    16
    19
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 322 (4.35%)
    17 / 320 (5.31%)
         occurrences all number
    15
    18

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2014
    Protocol Amendment A (dated 06 March 2014), revised the inclusion and exclusion criteria, modified stratification factors, and clarified several study procedures. The most significant amendment changes included: • Dosing change – the Fovista/Sham + Avastin group was changed from monthly in Year 1 followed by every other month in Year 2 with option for retreatment on the non-dosing months according to VA was changed to monthly treatment during both Year 1 and Year 2; the Fovista/Sham + Eylea group was changed from monthly in Year 1 followed by every other month in Year 2 with option for retreatment on the non-dosing months according to VA was changed to every month for the first 3 doses followed by every other month for the remainder of the study for up to 2 years. The changes were to reflect both EU and US prescribing recommendations. • Other sections were updated for clarification and consistency with dosing changes as outlined above.

    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.
    Given the lack of efficacy after one year of treatment, the OPH1004 study was prematurely terminated by the Sponsor during the second year of the study.
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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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