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    Clinical Trial Results:
    A dose-ranging study of intravitreal OPT-302 in combination with Ranibizumab, compared with Ranibizumab alone, in participants with neovascular age-related macular degeneration (wet AMD)

    Summary
    EudraCT number
    		 2017-002698-20
    Trial protocol
    		 CZ   LV   GB   ES   IT  
    Global end of trial date
    14 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 May 2020
    First version publication date
    30 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OPT-302-1002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03345082
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Opthea Limited
    Sponsor organisation address
    650 Chapel Street, South Yarra, Australia, VIC 3141
    Public contact
    Clinical Development, Opthea Limited, 61 398260399, clare.price@opthea.com
    Scientific contact
    Clinical Development, Opthea Limited, 61 398260399, clare.price@opthea.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
    14 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine the efficacy of two different doses of intravitreal OPT-302 when administered in combination with ranibizumab in participants with wet AMD
    Protection of trial subjects
    This study was conducted in accordance with the International Council for Harmonization Guidelines for Good Clinical Practice and The Declaration of Helsinki as well as per United States (US) Food and Drug Administration (FDA) Human Participant Protection Regulations (Title 21 Code of Federal Regulations, Parts 50, 54, 56 & 312) and local regulations in each of the participating countries. Written informed consent was to be obtained from each potential study participant prior to the initiation of any study-related procedures. The investigator or designee had to explain to each participant the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits involved, and any discomfort it may entail, and the alternative treatment options including standard of care. The information sheet accompanying the informed consent form (ICF) was to be given by means of a standard written statement, written in non-technical language, approved by the relevant IEC/IRB, and potential participants were to be given sufficient time to adequately read the information and properly consider the potential risks, benefits, study-specific procedures and time commitments. The participant was to read and consider the consent statement before signing and dating it. A copy of the signed document was to be given to the participant and the original was to be retained by the investigator.
    Background therapy
    		 All concomitant medications were to be reported and recorded in the eCRF (including prescribed and over-the-counter medications, vitamins, herbal remedies, other traditional preparations and any ocular preparations administered of any type) from the first Screening Visit through to the Week 24 Visit. Procedural medications, as mandated by the protocol, were not to be reported as concomitant medications. Additionally, use of restricted or excluded medications were to be recorded if they were used within the excluded periods prior to Screening. Where an ocular product or therapy was administered, the site of administration had to be included i.e., OD, OS or oculus uterque (OU; both eyes). The generic or trade name was to be recorded in the eCRF for products with one active ingredient.
    Evidence for comparator
    		 Sham intravitreal injection, with ranibizumab 0.5 mg (50 μL), by intravitreal injection.
    Actual start date of recruitment
    09 Nov 2017
    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
    United States: 165
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Israel: 46
    Country: Number of subjects enrolled
    Poland: 37
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Latvia: 22
    Worldwide total number of subjects
    366
    EEA total number of subjects
    155
    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)
    31
    From 65 to 84 years
    254
    85 years and over
    81

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multicentre, randomised, parallel-group, sham-controlled, double-masked, dose-ranging study. Eligible participants were randomised to one of three treatment groups in a 1:1:1 ratio: intravitreal Ranibizumab 0.5 mg followed by OPT-302 0.5 mg or OPT-302 2.0 mg and intravitreal Ranibizumab 0.5 mg followed by a sham injection.

    Pre-assignment
    Screening details
    		 Screening included fundus imaging review by an Independent Reading Centre.

    Period 1
    Period 1 title
    Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Randomisation and double-masking were used to minimise bias arising from the assignment of participants to treatment groups, and the expectations of participants, investigators and individuals collecting data.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ranibizumab 0.5 mg + OPT-302 0.5 mg
    Arm description
    		 Administered Ranibizumab 0.5 mg (50 μL) by intravitreal injection followed by OPT-302 0.5 mg (50 μL) by intravitreal injection. Administration was done every 4 weeks for 6 treatment cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Ranibizumab 0.5 mg solution for injection in prefilled syringe. Ranibizumab intravitreal injection was to be administered before the OPT-302 intravitreal injection. Intravitreal injection was given once every 4 weeks for six treatment cycles.

    Investigational medicinal product name
    OPT-302
    Investigational medicinal product code
    OPT-302
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    OPT-302 0.5 mg solution for injection for intravitreal use. OPT-302 intravitreal injection was to be administered after Ranibizumab intravitreal injection. Intravitreal injection was given once every 4 weeks for six treatment cycles.

    Arm title
    		 Ranibizumab 0.5 mg + OPT-302 2.0 mg
    Arm description
    		 Administered Ranibizumab 0.5 mg (50 μL) by intravitreal injection followed by OPT-302 2.0 mg (50 μL) by intravitreal injection. Administration was done every 4 weeks for 6 treatment cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Ranibizumab 0.5 mg solution for injection in pre-filled syringe. Ranibizumab intravitreal injection was to be administered before the OPT-302 intravitreal injection. Intravitreal injection was given once every 4 weeks for six treatment cycles.

    Investigational medicinal product name
    OPT-302
    Investigational medicinal product code
    OPT-302
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    OPT-302 2 mg solution for injection for intravitreal use. OPT-302 intravitreal injection was to be administered after Ranibizumab intravitreal injection. Intravitreal injection was given once every 4 weeks for six treatment cycle.

    Arm title
    		 Ranibizumab 0.5 mg + Sham
    Arm description
    		 Administered Ranibizumab 0.5 mg (50 μL) by intravitreal injection followed by a sham intravitreal injection. Administration was done every 4 weeks for 6 treatment cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Ranibizumab 0.5 mg solution for injection in pre-filled syringe. Ranibizumab intravitreal injection was to be administered before sham injection procedure. Intravitreal injection was given once every 4 weeks for six treatment cycles.

    Investigational medicinal product name
    Sham injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Sham intravitreal injection was to be administered after Ranibizumab intravitreal injection. Intravitreal injection was given once every 4 weeks for six treatment cycles.

    Number of subjects in period 1
    		Ranibizumab 0.5 mg + OPT-302 0.5 mg Ranibizumab 0.5 mg + OPT-302 2.0 mg Ranibizumab 0.5 mg + Sham
    Started
    122
    123
    121
    Completed
    112
    120
    116
    Not completed
    10
    3
    5
         Adverse event, serious fatal
    -
    -
    2
         Personal reasons
    1
    -
    -
         Consent withdrawn by subject
    7
    3
    2
         Withdrawn by the investigator
    -
    -
    1
         Lost to follow-up
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ranibizumab 0.5 mg + OPT-302 0.5 mg
    Reporting group description
    		 Administered Ranibizumab 0.5 mg (50 μL) by intravitreal injection followed by OPT-302 0.5 mg (50 μL) by intravitreal injection. Administration was done every 4 weeks for 6 treatment cycles.

    Reporting group title
    Ranibizumab 0.5 mg + OPT-302 2.0 mg
    Reporting group description
    		 Administered Ranibizumab 0.5 mg (50 μL) by intravitreal injection followed by OPT-302 2.0 mg (50 μL) by intravitreal injection. Administration was done every 4 weeks for 6 treatment cycles.

    Reporting group title
    Ranibizumab 0.5 mg + Sham
    Reporting group description
    		 Administered Ranibizumab 0.5 mg (50 μL) by intravitreal injection followed by a sham intravitreal injection. Administration was done every 4 weeks for 6 treatment cycles.

    Reporting group values
    		 Ranibizumab 0.5 mg + OPT-302 0.5 mg Ranibizumab 0.5 mg + OPT-302 2.0 mg Ranibizumab 0.5 mg + Sham Total
    Number of subjects
    		 122 123 121 366
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 7 11 13 31
        From 65-84 years
    		 85 86 83 254
        85 years and over
    		 30 26 25 81
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 78.8 (58 to 94) 77.8 (55 to 95) 76.1 (53 to 98) -
    Gender categorical
    Units: Subjects
        Female
    		 73 78 73 224
        Male
    		 49 45 48 142
    Subject analysis sets

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population comprised all participants in the ITT population but excluded those who did not receive at least one dose of study product, i.e., OPT-302 and/or Ranibizumab. 365 subjects were treated (safety population). This population was employed to determine the safety endpoints.

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population was to include all participants who were randomized into the study, irrespective of whether study product was administered or not. 366 subjects were randomized. This population was used to report participant disposition and to provide a sensitivity analysis of the primary endpoint only.

    Subject analysis set title
    Modified intent-to-treat (mITT) population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intent-to-treat (mITT) population comprised all participants in the safety population but excluded any participant without a Baseline visual acuity score and/or any participant who did not return for at least one post-Baseline visit. mITT population included 362 subjects. This population was employed for all efficacy analyses.

    Subject analysis sets values
    		 Safety population Intent-to-treat (ITT) population Modified intent-to-treat (mITT) population
    Number of subjects
    365
    366
    362
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    31
    31
    31
        From 65-84 years
    253
    254
    250
        85 years and over
    81
    81
    81
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    77.6 (53 to 98)
    77.6 (53 to 98)
    77.6 (53 to 98)
    Gender categorical
    Units: Subjects
        Female
    223
    224
    221
        Male
    142
    142
    141

    End points

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    End points reporting groups
    Reporting group title
    Ranibizumab 0.5 mg + OPT-302 0.5 mg
    Reporting group description
    		 Administered Ranibizumab 0.5 mg (50 μL) by intravitreal injection followed by OPT-302 0.5 mg (50 μL) by intravitreal injection. Administration was done every 4 weeks for 6 treatment cycles.

    Reporting group title
    Ranibizumab 0.5 mg + OPT-302 2.0 mg
    Reporting group description
    		 Administered Ranibizumab 0.5 mg (50 μL) by intravitreal injection followed by OPT-302 2.0 mg (50 μL) by intravitreal injection. Administration was done every 4 weeks for 6 treatment cycles.

    Reporting group title
    Ranibizumab 0.5 mg + Sham
    Reporting group description
    		 Administered Ranibizumab 0.5 mg (50 μL) by intravitreal injection followed by a sham intravitreal injection. Administration was done every 4 weeks for 6 treatment cycles.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population comprised all participants in the ITT population but excluded those who did not receive at least one dose of study product, i.e., OPT-302 and/or Ranibizumab. 365 subjects were treated (safety population). This population was employed to determine the safety endpoints.

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population was to include all participants who were randomized into the study, irrespective of whether study product was administered or not. 366 subjects were randomized. This population was used to report participant disposition and to provide a sensitivity analysis of the primary endpoint only.

    Subject analysis set title
    Modified intent-to-treat (mITT) population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intent-to-treat (mITT) population comprised all participants in the safety population but excluded any participant without a Baseline visual acuity score and/or any participant who did not return for at least one post-Baseline visit. mITT population included 362 subjects. This population was employed for all efficacy analyses.

    Primary: Mean change from Baseline in ETDRS BCVA letters to Week 24 (Visit 8)

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    End point title
    		 Mean change from Baseline in ETDRS BCVA letters to Week 24 (Visit 8)
    End point description
    The primary efficacy outcome measure was changed in ETDRS BCVA at Week 24. Participants in the higher dose (OPT-302 2.0 mg) group showed a greater mean gain in ETDRS BCVA letters at Week 24 compared with sham (+14.22 vs. +10.84 letters) and this difference was statistically significant. Thus, the study met its primary endpoint in the higher dose group whilst the lower dose (OPT-302 0.5 mg) group was similar to sham. Intravitreal OPT-302 2.0 mg administered with Ranibizumab significantly improved mean visual acuity compared with Ranibizumab alone.
    End point type
    Primary
    End point timeframe
    The primary endpoint is mean change from Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) best corrected visual acuity (BCVA) to Week 24 (Visit 8). It was based on the mITT population.
    End point values
    		 Ranibizumab 0.5 mg + OPT-302 0.5 mg Ranibizumab 0.5 mg + OPT-302 2.0 mg Ranibizumab 0.5 mg + Sham
    Number of subjects analysed
    122
    121
    119
    Units: Observed values (letters)
        least squares mean (standard error)
    9.44 ( 1.07 )
    14.22 ( 1.06 )
    10.84 ( 1.07 )
    Statistical analysis title
    		 SAS Version 9.4 (or later)
    Statistical analysis description
    Descriptive statistics included categorical data which were summarised in contingency tables presenting frequencies and percentages, and continuous data which were summarised number of missing values (Nmissing), number of non-missing values (n), mean, standard deviation (SD), standard error of the mean (SEM), 95% confidence interval (CI), median, minimum and maximum values.
    Comparison groups
    Ranibizumab 0.5 mg + OPT-302 0.5 mg v Ranibizumab 0.5 mg + OPT-302 2.0 mg v Ranibizumab 0.5 mg + Sham
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Control of Alpha
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 6.27
    Variability estimate
    Standard deviation
    Notes
    [1] - In order to preserve the level of significance, multiple comparisons were controlled using a Hochberg procedure. 95% confidence interval (CI) was constructed based on a Model for Repeated Measures which took into account the presence of missing data and yielded valid estimates under the assumption of data Missing at Random. With this procedure, the experiment-wise type I error rate was controlled at α (=0.05).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event reporting was to begin from initiation of Screening (i.e., from the signing of the ICF) and continue throughout the study until the final study visit.
    Adverse event reporting additional description
    A Data and Safety Monitoring Board was chartered to monitor the safety of all participants in this study by periodically reviewing unmasked summaries of safety data and assessing whether it was safe for the study to continue. The incidence of potentially related treatment-emergent adverse events (TEAEs) was similar across the three groups.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Ranibizumab 0.5 mg + OPT-302 0.5 mg
    Reporting group description
    		 -

    Reporting group title
    Ranibizumab 0.5 mg + OPT-302 2.0 mg
    Reporting group description
    		 -

    Reporting group title
    Ranibizumab 0.5 mg + Sham
    Reporting group description
    		 -

    Serious adverse events
    		 Ranibizumab 0.5 mg + OPT-302 0.5 mg Ranibizumab 0.5 mg + OPT-302 2.0 mg Ranibizumab 0.5 mg + Sham
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 120 (13.33%)
    9 / 124 (7.26%)
    10 / 121 (8.26%)
         number of deaths (all causes)
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal cancer
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 124 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 124 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism arterial
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 124 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Gastric operation
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Corneal graft rejection
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic rhinosinusitis with nasal polyps
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 124 (0.81%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural vomiting
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 124 (0.81%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 124 (0.00%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 124 (0.81%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 120 (0.00%)
    2 / 124 (1.61%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 124 (0.81%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 124 (0.81%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 124 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Corneal decompensation
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitritis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 124 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 124 (0.81%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Colonic abscess
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 124 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 124 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 124 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 124 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 124 (0.81%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 124 (0.81%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 124 (0.81%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ranibizumab 0.5 mg + OPT-302 0.5 mg Ranibizumab 0.5 mg + OPT-302 2.0 mg Ranibizumab 0.5 mg + Sham
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    86 / 120 (71.67%)
    79 / 124 (63.71%)
    66 / 121 (54.55%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    7 / 120 (5.83%)
    6 / 124 (4.84%)
    2 / 121 (1.65%)
         occurrences all number
    7
    6
    2
    Eye disorders
    Eye pain
         subjects affected / exposed
    25 / 120 (20.83%)
    18 / 124 (14.52%)
    20 / 121 (16.53%)
         occurrences all number
    25
    18
    20
    Conjunctival haemorrhage
         subjects affected / exposed
    20 / 120 (16.67%)
    17 / 124 (13.71%)
    16 / 121 (13.22%)
         occurrences all number
    20
    17
    16
    Vitreous floaters
         subjects affected / exposed
    11 / 120 (9.17%)
    9 / 124 (7.26%)
    5 / 121 (4.13%)
         occurrences all number
    11
    9
    5
    Eye irritation
         subjects affected / exposed
    8 / 120 (6.67%)
    8 / 124 (6.45%)
    7 / 121 (5.79%)
         occurrences all number
    8
    8
    7
    Foreign body sensation in eyes
         subjects affected / exposed
    4 / 120 (3.33%)
    4 / 124 (3.23%)
    8 / 121 (6.61%)
         occurrences all number
    4
    4
    8
    Lacrimation increased
         subjects affected / exposed
    5 / 120 (4.17%)
    7 / 124 (5.65%)
    3 / 121 (2.48%)
         occurrences all number
    5
    7
    3
    Ocular hyperaemia
         subjects affected / exposed
    6 / 120 (5.00%)
    4 / 124 (3.23%)
    3 / 121 (2.48%)
         occurrences all number
    6
    4
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2017
    Amendment 1, dated 23rd November 2017 (Protocol Version 2.0) - was released only in the US and Israel. Sections of the protocol including primary, secondary and exploratory objectives and endpoints, eligibility criteria, study procedures for discontinuation and pregnancy were further clarified. The Risk Assessment was updated with information concerning a bilateral amaurosis reported during Study OPT-302-1001 and potential teratogenicity of the anti-VEGF class of drugs. Progression of wet AMD in the Study Eye was added to the list of medical events that was to be reported as an AE. The facility to allow enrolment of additional participants if the calculated SD was significantly greater than the assumed SD; and/or if the overall rate of participants eligible for the mITT population was lower than estimated, was removed. Additional information on the approach to subgroup analyses were added to the efficacy analysis.
    13 Dec 2017
    Amendment, dated 13th December 2017 (Protocol Version 2.1) - was released and approved in the European countries only. Protocol Version 2.1 included all changes as per Protocol Version 2.0 with the following additional change: The option to store investigational product in a temperature-monitored refrigerator between 2°C to 8°C [35°F to 46°F]) was removed for European sites. Product was only to be stored in a temperature-monitored freezer (between -25°C to -15°C [-13°F to 5°F]).

    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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