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    Clinical Trial Results:
    A Multicentre Phase III Double-masked Randomised Controlled Non-Inferiority Trial comparing the clinical and cost effectiveness of intravitreal therapy with ranibizumab (Lucentis) vs aflibercept (Eylea) vs bevacizumab (Avastin) for Macular Oedema due to Central Retinal Vein Occlusion (CRVO).

    Summary
    EudraCT number
    		 2014-000272-26
    Trial protocol
    		 GB  
    Global end of trial date
    21 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Apr 2020
    First version publication date
    25 Apr 2020
    Other versions
    Summary report(s)
    		 End of study summary report

    Trial information

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    Trial identification
    Sponsor protocol code
    HYKP1021
    Additional study identifiers
    ISRCTN number
    		 ISRCTN13623634
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Moorfields Eye Hospital NHS Foundation Trust
    Sponsor organisation address
    162 City Road, London, United Kingdom, EC1V 2PD
    Public contact
    Tania West, Moorfields Eye Hospital NHS Foundation Trust, 44 020 7253 3411 x2937 ,
    Scientific contact
    Tania West, Moorfields Eye Hospital NHS Foundation Trust, 44 02072533411, moorfields.resadmin@nhs.net
    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
    21 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if bevacizumab or afilbercept are as effective as ranibizumab in reducing visual loss from MO due to CRVO, whether they have an equivalent side effect profile and whether either could be considered as a recommended NHS treatment based on non-inferior clinical effectiveness and superior cost-effectiveness to ranibizumab.
    Protection of trial subjects
    Patients were fully consented following adequate explanation of the aims, methods, anticipated benefits and potential hazards of the study. They were advised that any data collected were held and used in accordance with the Data Protection Act 1998. Patients were given at least 24 hours after receiving the PIS to consider taking part. Data was anonymized and stored securely. Complications such as the development of ischaemic CRVO, NVA, NVI, NVG, NVE and NVD in the study eye were recorded as adverse events. Diagnosis and management of these complications of CRVO in the study was based on investigator discretion and local practice. The MHRA definitions of adverse and serious adverse events were adopted for this trial. Adverse events were reported by the site in the adverse events log in the eCRF. All SAEs, SARs & SUSARs were recorded and reported on the serious adverse event form to the Chief Investigator / delegate within 24 hours of learning of their occurrence. The trial had a designated Trial Steering Committee which was responsible for monitoring the overall integrity, conduct and safety of the trial and an independent Data Monitoring and Ethics Committee to safeguard the interests of trial participants, assess the safety and efficacy of the interventions during the trial, and monitor the overall conduct of the clinical trial. The study would have been discontinued on the basis of new safety information, or for other reasons given by the DMEC and/or TSC, Sponsor, regulatory authority or Research Ethics Committee concerned. All members of the research team were compliant with Good Clinical Practice guidelines.
    Background therapy
    		 Retinal laser therapy was used for complications such as ischaemic CRVO, NVA, NVI, NVG, NVE and NVD.
    Evidence for comparator
    		 First line therapy of macular oedema is repeated intravitreal injections of anti-VEGF agents to block the action of VEGF thus reducing capillary permeability. Ranibizumab was licensed by the FDA and EMA for MO due to CRVO in 2012 based on the CRUISE study data that showed monthly intraocular ranibizumab therapy improved mean BCVA by +15 ETDRS letters at 6 months and a PRN regimen with monthly monitoring improved mean BCVA by +14 letters at 12 months. Aflibercept was FDA and EMA licensed for CRVO in 2014 based on the GALILEO and COPERNICUS studies that showed a mean gain of +16.2 letters BVCA at 12 and +13.0 at 24 months. Despite these results and that it was non-inferior to ranibizumab when given 8 weekly after a loading phase in nvAMD suggesting improved cost effectiveness, no clinical trial had been undertaken to directly compare it with ranibizumab or bevacizumab even though NICE recommended it for MO due to CRVO (NICE TA305). Bevacizumab is EMA licensed for the treatment of cancer but is used off-label in the eye. It is substantially cheaper than ranibizumab or aflibercept and has been used in private practice and NHS trusts across the UK for nvAMD, DMO and RVO and other less common indications such as choroidal neovascularisation due to myopia and retinal dystrophies. It was found to be non-inferior to ranibizumab in the IVAN and CATT studies. There have been concerns about the possible systemic side effects following intraocular injection of bevacizumab. The NICE TAG 283: Lucentis (ranibizumab) and the TAG 305: Eylea (aflibercept) for MO secondary to CRVO recommended that further head to head trials including bevacizumab were needed for RVO that carefully examined clinical and cost effectiveness. It was therefore proposed to conduct the LEAVO trial in MO due to CRVO to compare the clinical and cost effectiveness of ranibizumab, aflibercept and bevacizumab, and describe the safety profile of each with ocular and systemic adverse events over 24 months.
    Actual start date of recruitment
    03 Dec 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
    United Kingdom: 463
    Worldwide total number of subjects
    463
    EEA total number of subjects
    463
    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)
    138
    From 65 to 84 years
    284
    85 years and over
    41

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment commenced from 1st December 2014 and the last patient was randomised 16th December 2016. 586 patients were assessed across 44 UK NHS Hospitals, of which 463 eligible patients were randomly assigned to receive ranibizumab (n=155), aflibercept (n=154) or bevacizumab (n=154).

    Pre-assignment
    Screening details
    		 Demographic data, medical history and ophthalmic history were obtained at screening. Refracted ETDRS visual acuity, undilated examinations for NVI, IOP and RAPD along with dilated fundus examination, SD-OCT, colour fundus photography and fluorescein angiogram were performed. Health economic questionnaires were administered.

    Pre-assignment period milestones
    Number of subjects started
    		 463
    Number of subjects completed
    		 463

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Only the pharmacy at the local trial site, the emergency unmasking service and unmasked trial management staff were informed of the treatment arm. The study drug was transferred in a sealed opaque masking bag to the dedicated injection room. The unmasked injector opened the bag and placed the medication out of sight of the patient before they entered the room. There was no record of the subjects’ treatment arm in the source notes or case report form

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ranibizumab arm
    Arm description
    		 -
    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
    Dosage and route - 0.5mg/50ul intravitreal injection. After mandated administration at baseline, 4, 8, and 12 weeks, further PRN intervention was administered at weeks 16 and 20 if retreatment criteria were met and VA ≤ 83 letters. Whether a treatment was given or not, the patient was reviewed in 4 weeks. From week 24 to week 96, intervals were initially 4 weekly (with a -14 to + 14 day visit window) with the potential to increase to 8 weekly (with a -14 to + 14 day visit window) if criteria for ‘Stability’ were achieved. Treatment was not given if success criteria (from week 16 onwards) or non-responder treatment suspension criteria ( from week 24 onwards) were met. Treatment could be restarted at a later visit if defined criteria were met. Deferral of treatment was allowed under certain circumstances.

    Arm title
    		 Aflibercept arm
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Eylea
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Dosage and route - 2.0mg/50ul intravitreal injection. After mandated administration at baseline, 4, 8, and 12 weeks, further PRN intervention was administered at weeks 16 and 20 if retreatment criteria were met and VA ≤ 83 letters. Whether a treatment was given or not, the patient was reviewed in 4 weeks. From week 24 to week 96, intervals were initially 4 weekly (with a -14 to + 14 day visit window) with the potential to increase to 8 weekly (with a -14 to + 14 day visit window) if criteria for ‘Stability’ were achieved. Treatment was not given if success criteria (from week 16 onwards) or non-responder treatment suspension criteria ( from week 24 onwards) were met. Treatment could be restarted at a later visit if defined criteria were met. Deferral of treatment was allowed under certain circumstances.

    Arm title
    		 Bevacizumab arm
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab arm
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Dosage and route - 1.25mg/50ul intravitreal injection. After mandated administration at baseline, 4, 8, and 12 weeks, further PRN intervention was administered at weeks 16 and 20 if retreatment criteria were met and VA ≤ 83 letters. Whether a treatment was given or not, the patient was reviewed in 4 weeks. From week 24 to week 96, intervals were initially 4 weekly (with a -14 to + 14 day visit window) with the potential to increase to 8 weekly (with a -14 to + 14 day visit window) if criteria for ‘Stability’ were achieved. Treatment was not given if success criteria (from week 16 onwards) or non-responder treatment suspension criteria ( from week 24 onwards) were met. Treatment could be restarted at a later visit if defined criteria were met. Deferral of treatment was allowed under certain circumstances.

    Number of subjects in period 1
    		Ranibizumab arm Aflibercept arm Bevacizumab arm
    Started
    155
    154
    154
    Completed
    135
    133
    139
    Not completed
    20
    21
    15
         Adverse event, serious fatal
    3
    6
    4
         Moved away
    -
    2
    1
         Consent withdrawn by subject
    8
    6
    5
         Adverse event, non-fatal
    2
    1
    2
         Health deterioration
    2
    -
    -
         Lost to follow-up
    3
    3
    1
         Deterioration of health
    -
    2
    1
         not specified
    2
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ranibizumab arm
    Reporting group description
    		 -

    Reporting group title
    Aflibercept arm
    Reporting group description
    		 -

    Reporting group title
    Bevacizumab arm
    Reporting group description
    		 -

    Reporting group values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm Total
    Number of subjects
    		 155 154 154 463
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.2 ± 13.0 68.7 ± 13.2 69.3 ± 12.8 -
    Gender categorical
    Units: Subjects
        Female
    		 70 60 68 198
        Male
    		 85 94 86 265
    BCVA letter score in the study eye
    Units: Subjects
        19-38
    		 31 27 27 85
        39-58
    		 56 55 55 166
        59-78
    		 68 72 72 212
    Lens Status, (study eye)
    Units: Subjects
        Cataract
    		 41 44 46 131
        Pseudophakia
    		 29 20 19 68
        Normal lens
    		 85 90 89 264
    Duration of study eye CRVO
    Units: Subjects
        <3 months
    		 134 129 138 401
        3-6 months
    		 11 19 8 38
        >6 months
    		 10 6 8 24
    Previous treatment study eye
    Units: Subjects
        Nil
    		 148 149 149 446
        anti-VEGF therapy
    		 6 5 5 16
        not recorded
    		 1 0 0 1
    CRVO ischaemic status at baseline
    Units: Subjects
        Non-ischaemic
    		 137 135 134 406
        Ischaemic
    		 17 19 20 56
        not recorded
    		 1 0 0 1
    Mean BCVA letter score in the study eye
    For one participant in each arm the baseline best refracted visual acuity test was incomplete /test was not performed.
    Units: ETDRS letters
        arithmetic mean (standard deviation)
    		 53.6 ± 15.1 54.1 ± 15.3 54.4 ± 14.2 -
    OCT (study eye)
    Central subfield thickness
    Units: µm
        arithmetic mean (standard deviation)
    		 731.3 ± 227.6 673.2 ± 189.4 676.1 ± 207.0 -
    Median duration of CRVO
    Units: months
        median (inter-quartile range (Q1-Q3))
    		 0.9 (0.5 to 1.8) 0.9 (0.4 to 1.7) 0.9 (0.4 to 1.7) -
    OCT Study eye - Total volume
    For Total Volume, data was missing for two ranibizumab patients and one bevacizumab patient.
    Units: mm3
        arithmetic mean (standard deviation)
    		 13 ± 2.9 12.3 ± 2.6 12.8 ± 2.9 -
    Systolic blood pressure
    Not recorded for one ranibizumab patient randomized in error
    Units: mmHg
        arithmetic mean (standard deviation)
    		 143.1 ± 17.6 142.6 ± 17.0 143.1 ± 15.7 -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 80.1 ± 10.2 79.1 ± 10.6 79.9 ± 10.6 -

    End points

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    End points reporting groups
    Reporting group title
    Ranibizumab arm
    Reporting group description
    		 -

    Reporting group title
    Aflibercept arm
    Reporting group description
    		 -

    Reporting group title
    Bevacizumab arm
    Reporting group description
    		 -

    Primary: Mean gain in BCVA letter score at 100 weeks - intention to treat

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    End point title
    		 Mean gain in BCVA letter score at 100 weeks - intention to treat
    End point description
    End point type
    Primary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    135
    133
    139
    Units: ETDRS Letters
        arithmetic mean (standard deviation)
    12.5 ± 21.1
    15.1 ± 18.7
    9.8 ± 21.4
    Statistical analysis title
    		 Aflibercept vs Ranibizumab (Intention to Treat)
    Statistical analysis description
    The 95% CI for the adjusted mean difference in BCVA letter score between arms at 100 weeks was calculated. Intention to treat strategy Outcome data was valid and included if the BCVA measure was refracted. All randomised subjects who provided at least one post-baseline valid measurement were included
    Comparison groups
    Ranibizumab arm v Aflibercept arm
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.0006 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.17
         upper limit
    		 6.63
    Notes
    [1] - Non-inferiority was only concluded if this was declared by both the ITT analysis and the PP analysis at 100 weeks. Non-inferiority was declared if the estimated 95% confidence interval for the difference in means lies wholly above the margin of -5 letters in both ITT and PP analysis models primarily at 100 weeks and secondarily at 52 weeks. The linear mixed-effects model incorporates 301 participants (n=148 ranibizumab and n=153 aflibercept) with best corrected visual acuity at 100 weeks.
    [2] - p-value for non-inferiority - p<0.025 is significant
    Statistical analysis title
    		 Bevacizumab vs Ranibizumab - Intention to treat
    Statistical analysis description
    The 95% CI for the adjusted mean difference in BCVA letter score between arms at 100 weeks was calculated. Intention to treat strategy Outcome data was valid and included if the BCVA measure was refracted. All randomised subjects who provided at least one post-baseline valid measurement were included
    Comparison groups
    Ranibizumab arm v Bevacizumab arm
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.071 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.12
         upper limit
    		 2.67
    Notes
    [3] - Non-inferiority was only concluded if this was declared by both the ITT analysis and the PP analysis at 100 weeks. Non-inferiority was declared if the estimated 95% confidence interval for the difference in means lies wholly above the margin of -5 letters in both ITT and PP analysis models primarily at 100 weeks and secondarily at 52 weeks. The linear mixed-effects model incorporates 301 participants (n=148 ranibizumab, n=153 bevacizumab) with best corrected visual acuity at 100 weeks.
    [4] - p-value for non-inferiority - p<0.025 is significant

    Primary: Mean BCVA -100 weeks (per protocol)

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    End point title
    		 Mean BCVA -100 weeks (per protocol)
    End point description
    End point type
    Primary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    133
    128
    139
    Units: Letter score
        arithmetic mean (standard error)
    65.7 ± 1.7
    69.5 ± 1.5
    64.6 ± 1.8
    Statistical analysis title
    		 Aflibercept versus Ranibizumab (per protocol)
    Statistical analysis description
    The 95% CI for the adjusted mean difference in BCVA letter score between arms at 100 weeks was calculated. Per protocol strategy The per protocol (PP) population was defined as a subset of the ITT population who were eligible and received minimal sufficient treatment exposure defined as four treatments correctly assessed and received during the first six visits. For the analysis of the primary outcome, the mixed effects model was re-fitted within the PP population.
    Comparison groups
    Ranibizumab arm v Aflibercept arm
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted difference
    Point estimate
    3.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 7.88
    Notes
    [5] - Non-inferiority was only concluded if this was declared by both the ITT analysis and the PP analysis at 100 weeks. Non-inferiority was declared if the estimated 95% confidence interval for the difference in means lies wholly above the margin of -5 letters in both ITT and PP analysis models primarily at 100 weeks and secondarily at 52 weeks. The linear mixed-effects model incorporates 291 participants (n=145 ranibizumab, n=146 aflibercept) with best corrected visual acuity at 100 weeks.
    [6] - p-value for non-inferiority - p<0.025 is significant
    Statistical analysis title
    		 Bevacizumab vs Ranibizumab (per protocol)
    Statistical analysis description
    The 95% CI for the adjusted mean difference in BCVA letter score between arms at 100 weeks was calculated. Per protocol strategy The per protocol (PP) population was defined as a subset of the ITT population who were eligible and received minimal sufficient treatment exposure defined as four treatments correctly assessed and received during the first six visits. For the analysis of the primary outcome, the mixed effects model was re-fitted within the PP population.
    Comparison groups
    Ranibizumab arm v Bevacizumab arm
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 = 0.066 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted difference
    Point estimate
    -1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.02
         upper limit
    		 2.68
    Notes
    [7] - Non-inferiority was only concluded if this was declared by both the ITT analysis and the PP analysis at 100 weeks. Non-inferiority was declared if the estimated 95% confidence interval for the difference in means lies wholly above the margin of -5 letters in both ITT and PP analysis models primarily at 100 weeks and secondarily at 52 weeks. The linear mixed-effects model incorporates 297 participants (n=145 ranibizumab, n=152 bevacizumab) with best corrected visual acuity at 100 weeks.
    [8] - p-value for non-inferiority - p<0.025 is significant

    Secondary: Mean best corrected visual acuity at 52 weeks - Intention to treat

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    End point title
    		 Mean best corrected visual acuity at 52 weeks - Intention to treat
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    139
    139
    135
    Units: ETDRS letters
        arithmetic mean (standard error)
    65.4 ± 1.6
    67.2 ± 1.5
    66.4 ± 1.6
    Statistical analysis title
    		 Ranibizumab vs Aflibercept
    Statistical analysis description
    The 95% CI for the adjusted mean difference in BCVA letter score between arms at 52 weeks was calculated. Intention to treat strategy Outcome data was valid and included if the BCVA measure was refracted. All randomised subjects who provided at least one post-baseline valid measurement were included
    Comparison groups
    Ranibizumab arm v Aflibercept arm
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    P-value
    		 = 1.33 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted difference
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.62
         upper limit
    		 5.28
    Notes
    [9] - Non-inferiority was only concluded if this was declared by both the ITT analysis and the PP analysis at 100 weeks. Non-inferiority was declared if the estimated 95% confidence interval for the difference in means lies wholly above the margin of -5 letters in both ITT and PP analysis models primarily at 100 weeks and secondarily at 52 weeks. The linear mixed-effects model incorporates 301 participants (n=148 ranibizumab, n=153 aflibercept) with best corrected visual acuity at 52 weeks.
    [10] - p-value for non-inferiority - p<0.025 is significant
    Statistical analysis title
    		 Ranibizumab vs bevacizumab
    Statistical analysis description
    The 95% CI for the adjusted mean difference in BCVA letter score between arms at 52 weeks was calculated. Intention to treat strategy Outcome data was valid and included if the BCVA measure was refracted. All randomised subjects who provided at least one post-baseline valid measurement were included
    Comparison groups
    Ranibizumab arm v Bevacizumab arm
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    P-value
    		 = 0.0067 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted difference
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.97
         upper limit
    		 3.94
    Notes
    [11] - Non-inferiority was only concluded if this was declared by both the ITT analysis and the PP analysis at 100 weeks. Non-inferiority was declared if the estimated 95% confidence interval for the difference in means lies wholly above the margin of -5 letters in both ITT and PP analysis models primarily at 100 weeks and secondarily at 52 weeks. The linear mixed-effects model incorporates 301 participants (n=148 ranibizumab, n=153 bevacizumab) with best corrected visual acuity at 52 weeks
    [12] - p-value for non-inferiority - p<0.025 is significant

    Secondary: Mean best corrected visual acuity at 52 weeks - per protocol

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    End point title
    		 Mean best corrected visual acuity at 52 weeks - per protocol
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    137
    133
    135
    Units: ETDRS letters
        arithmetic mean (standard error)
    65.5 ± 1.7
    68.4 ± 1.4
    66.4 ± 135
    Statistical analysis title
    		 Aflibercept versus Ranibizumab
    Statistical analysis description
    The 95% CI for the adjusted mean difference in BCVA letter score between arms at 52 weeks was calculated. Per protocol strategy The per protocol (PP) population was defined as a subset of the ITT population who were eligible and received minimal sufficient treatment exposure defined as four treatments correctly assessed and received during the first six visits. For the analysis of the primary outcome, the mixed effects model was re-fitted within the PP population.
    Comparison groups
    Aflibercept arm v Ranibizumab arm
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.0002 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted difference
    Point estimate
    2.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.81
         upper limit
    		 6.1
    Notes
    [13] - Non-inferiority was only concluded if this was declared by both the ITT analysis and the PP analysis at 100 weeks. Non-inferiority was declared if the estimated 95% confidence interval for the difference in means lies wholly above the margin of -5 letters in both ITT and PP analysis models primarily at 100 weeks and secondarily at 52 weeks. The linear mixed-effects model incorporates 291 participants (n=145 ranibizumab, n=146 aflibercept) with best corrected visual acuity at 52 weeks.
    [14] - p-value for non-inferiority - p<0.025 is significant
    Statistical analysis title
    		 Bevacizumab versus Ranibizumab
    Statistical analysis description
    The 95% CI for the adjusted mean difference in BCVA letter score between arms at 52 weeks was calculated. Per protocol strategy The per protocol (PP) population was defined as a subset of the ITT population who were eligible and received minimal sufficient treatment exposure defined as four treatments correctly assessed and received during the first six visits. For the analysis of the primary outcome, the mixed effects model was re-fitted within the PP population.
    Comparison groups
    Ranibizumab arm v Bevacizumab arm
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 = 0.0058 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.88
         upper limit
    		 3.98
    Notes
    [15] - Non-inferiority was only concluded if this was declared by both the ITT analysis and the PP analysis at 100 weeks. Non-inferiority was declared if the estimated 95% confidence interval for the difference in means lies wholly above the margin of -5 letters in both ITT and PP analysis models primarily at 100 weeks and secondarily at 52 weeks. The linear mixed-effects model incorporates 297 participants (n=145 ranibizumab, n=152 bevacizumab) with best corrected visual acuity at 52 weeks.
    [16] - p-value for non-inferiority - p<0.025 is significant

    Secondary: Patients with ≥10 ETDRS letter improvement at 100 weeks

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    End point title
    		 Patients with ≥10 ETDRS letter improvement at 100 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    133
    132
    138
    Units: Percentage
    63
    68
    63
    No statistical analyses for this end point

    Secondary: Patients with ≥10 ETDRS letter improvement at 52 weeks

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    End point title
    		 Patients with ≥10 ETDRS letter improvement at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    138
    138
    134
    Units: Percentage
    60
    62
    64
    No statistical analyses for this end point

    Secondary: Patients with <15 ETDRS letter decrease at 100 weeks

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    End point title
    		 Patients with <15 ETDRS letter decrease at 100 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    133
    132
    138
    Units: Percentage
    90
    93
    90
    No statistical analyses for this end point

    Secondary: Patients with <15 ETDRS letter decrease at 52 weeks

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    End point title
    		 Patients with <15 ETDRS letter decrease at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    138
    138
    134
    Units: percentage
    90
    93
    95
    No statistical analyses for this end point

    Secondary: Patients with ≥30 ETDRS letter decrease at 100 weeks

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    End point title
    		 Patients with ≥30 ETDRS letter decrease at 100 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    133
    132
    138
    Units: percentage
    5
    2
    6
    No statistical analyses for this end point

    Secondary: Patients with ≥ 30 ETDRS letter decrease at 52 weeks

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    End point title
    		 Patients with ≥ 30 ETDRS letter decrease at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    138
    138
    134
    Units: Percentage
    6
    1
    3
    No statistical analyses for this end point

    Secondary: Patients with ≥15 ETDRS letter improvement at 100 weeks

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    End point title
    		 Patients with ≥15 ETDRS letter improvement at 100 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    133
    132
    138
    Units: percentage
    47
    52
    45
    No statistical analyses for this end point

    Secondary: Patients with >73 ETDRS letter score (>20/40 Snellen equivalent) at 100 weeks

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    End point title
    		 Patients with >73 ETDRS letter score (>20/40 Snellen equivalent) at 100 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    135
    133
    139
    Units: Percentage
    47
    44
    41
    No statistical analyses for this end point

    Secondary: Patients with ≤58 ETDRS letter score (20/80) Snellen equivalent) at 100 weeks

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    End point title
    		 Patients with ≤58 ETDRS letter score (20/80) Snellen equivalent) at 100 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    135
    133
    139
    Units: Percentage
    39
    26
    42
    No statistical analyses for this end point

    Secondary: Patients with <19 ETDRS letter score (20/400 Snellen equivalent) at 100 weeks

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    End point title
    		 Patients with <19 ETDRS letter score (20/400 Snellen equivalent) at 100 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    135
    133
    139
    Units: Percentage
    4
    2
    6
    No statistical analyses for this end point

    Secondary: Patients with >73 ETDRS letter score (>20/40- Snellen equivalent) at 52 weeks.

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    End point title
    		 Patients with >73 ETDRS letter score (>20/40- Snellen equivalent) at 52 weeks.
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    139
    139
    135
    Units: Percentage
    42
    42
    39
    No statistical analyses for this end point

    Secondary: Patients with ≤58 ETDRS letter (≤20/80 Snellen equivalent) at 52 weeks

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    End point title
    		 Patients with ≤58 ETDRS letter (≤20/80 Snellen equivalent) at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    139
    139
    135
    Units: Percentage
    28
    25
    24
    No statistical analyses for this end point

    Secondary: Patients with <19letters ETDRS letter (20/400 Snellen equivalent) at 52 weeks

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    End point title
    		 Patients with <19letters ETDRS letter (20/400 Snellen equivalent) at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    139
    139
    135
    Units: Percentage
    5
    2
    5
    No statistical analyses for this end point

    Secondary: Mean change in OCT central subfield thickess from baseline to 100 weeks

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    End point title
    		 Mean change in OCT central subfield thickess from baseline to 100 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    135
    133
    139
    Units: microns
        arithmetic mean (confidence interval 95%)
    -405 (-450 to -360)
    -378 (-412 to -343)
    -334 (-374 to -293)
    Statistical analysis title
    		 Adjusted difference in CST at 100 weeks
    Statistical analysis description
    There were no clinically relevant differences across treatment groups for the adjusted difference in CST at 100 weeks
    Comparison groups
    Ranibizumab arm v Aflibercept arm
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -29.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -60.9
         upper limit
    		 2.3
    Statistical analysis title
    		 Adjusted difference in CST at 100 weeks
    Statistical analysis description
    There were no clinically relevant differences across treatment groups for the adjusted difference in CST at 100 weeks
    Comparison groups
    Ranibizumab arm v Bevacizumab arm
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    21.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.7
         upper limit
    		 53.4

    Secondary: Mean OCT macular volume at 100 weeks

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    End point title
    		 Mean OCT macular volume at 100 weeks
    End point description
    There was no difference in mean macular volume in each study group at 100 weeks
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    135
    133
    135
    Units: cubic millimetre
        arithmetic mean (standard error)
    8.9 ± 0.1
    8.6 ± 0.1
    9.1 ± 0.2
    Statistical analysis title
    		 Adjusted difference between groups at 100 weeks
    Statistical analysis description
    The linear mixed-effects model incorporates 455 participants (n=149 ranibizumab, n=153 aflibercept and n=153 bevacizumab and) with both CST and macular volume at either 52 weeks or 100 weeks.
    Comparison groups
    Ranibizumab arm v Aflibercept arm
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.3
    Statistical analysis title
    		 Adjusted difference between groups at 100 weeks
    Statistical analysis description
    The linear mixed-effects model incorporates 455 participants (n=149 ranibizumab, n=153 aflibercept and n=153 bevacizumab and) with both CST and macular volume at either 52 weeks or 100 weeks.
    Comparison groups
    Ranibizumab arm v Bevacizumab arm
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.7

    Secondary: Mean OCT macular volume at 52 weeks

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    End point title
    		 Mean OCT macular volume at 52 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    138
    140
    135
    Units: cubic millimetre
        arithmetic mean (standard error)
    9.2 ± 0.2
    9.1 ± 0.2
    9.4 ± 0.2
    Statistical analysis title
    		 Adjusted difference between groups at 52 weeks
    Statistical analysis description
    The linear mixed-effects model incorporates 455 participants (n=149 ranibizumab, n=153 aflibercept and n=153 bevacizumab and) with both CST and macular volume at either 52 weeks or 100 weeks.
    Comparison groups
    Ranibizumab arm v Aflibercept arm
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.4
    Statistical analysis title
    		 Adjusted difference between groups at 52 weeks
    Statistical analysis description
    The linear mixed-effects model incorporates 455 participants (n=149 ranibizumab, n=153 aflibercept and n=153 bevacizumab and) with both CST and macular volume at either 52 weeks or 100 weeks.
    Comparison groups
    Ranibizumab arm v Bevacizumab arm
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.7

    Secondary: Percentage of patients with OCT < 320um at 100 weeks

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    End point title
    		 Percentage of patients with OCT < 320um at 100 weeks
    End point description
    There was a significantly greater proportion of patients with OCT CST <320μm at 100 weeks for aflibercept (81%) compared to ranibizumab group (66%), 15.3% difference (95% CI 4.9 to 25.7)
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    135
    133
    135
    Units: Percentage
    66
    81
    59
    No statistical analyses for this end point

    Secondary: Percentage of patients with OCT < 320um at 52 weeks

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    End point title
    		 Percentage of patients with OCT < 320um at 52 weeks
    End point description
    There was a significantly greater proportion of patients with OCT CST <320μm at 52 weeks for aflibercept (76%), compared to ranibizumab (63%), a 12.4% difference (95% CI 1.7 to 23.1).
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    138
    140
    135
    Units: percentage
    63
    76
    53
    No statistical analyses for this end point

    Secondary: Mean number of injections across treatment groups - 100 weeks

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    End point title
    		 Mean number of injections across treatment groups - 100 weeks
    End point description
    The difference between aflibercept and ranibizumab groups was meaningful (mean difference week 100 -1.9 (95% CI -2.9 to -0.8))
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    135
    133
    139
    Units: number
        arithmetic mean (confidence interval 95%)
    11.8 (10.9 to 12.7)
    10.0 (9.3 to 10.6)
    11.5 (10.7 to 12.4)
    No statistical analyses for this end point

    Secondary: Change in retinal non-perfusion at 100 weeks.

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    End point title
    		 Change in retinal non-perfusion at 100 weeks.
    End point description
    The novel concentric ring method for analysing non-perfusion in disc areas and developed by the LEAVO group during the study was applicable in 235 of 463 patients randomised who underwent wide angled Optos fluorescein angiography. Of these 187 had images successfully performed at both entry and exit and of these 40 were not graded as they received PRP during the study (n=11), there were poor quality images either at baseline or exit (n=23) or the images were not corrected for peripheral angular distortion (n=6) leaving 147 gradable images. Of these 102 were gradable in more than 85% of the assessed area, were converted into disc areas of non perfusion and form the basis of the comparison.
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    40
    33
    30
    Units: disc areas
        median (inter-quartile range (Q1-Q3))
    0.0 (-5.6 to 16.6)
    6.5 (0.0 to 22.5)
    0.0 (-13.2 to 15.2)
    Attachments
    		 Amount of retinal non perfusion per arm and change
    No statistical analyses for this end point

    Secondary: Number with no 2 step worsening of non-perfusion on fluorescein angiography

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    End point title
    		 Number with no 2 step worsening of non-perfusion on fluorescein angiography
    End point description
    Of 463 patients at baseline, 461 underwent FFA. At 100 weeks, 407 completed the ITT analysis of whom 377 underwent FFA, and 30 did not as they declined, had experienced an adverse reaction to the dye at baseline, or there were intravenous cannulation / technical difficulties. Of the 377, 53 could not be graded for other reasons e.g. the patient had received panretinal photocoagulation before or during the study and in 14 all images were ungradable, leaving 310 patients with gradable images (table 13). The percentages of patients in each arm with ≥2 step worsening in one or more quadrants appeared more frequent in the aflibercept arm compared to bevacizumab but as the number of affected quadrants increased the result across arms tended to converge. Overall the data showed no meaningful difference between treatment groups in terms of the number of patients with at least 2-step worsening of non perfusion in one or more quadrant.
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    105
    96
    109
    Units: Number of patients
    73
    62
    86
    Attachments
    		 Untitled (Filename: Change in capillary non-perfusion (CNP).pdf)
    No statistical analyses for this end point

    Secondary: Proportion of patients who were persistent non-responders at 100 weeks

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    End point title
    		 Proportion of patients who were persistent non-responders at 100 weeks
    End point description
    Persistent non-responders were defined as not more than a 5 letter gain in VA and OCT CST decrease of less than 50 μm at 100 weeks.
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    135
    133
    139
    Units: Number
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Proportion with no evidence of macular oedema on OCT - 100 weeks

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    End point title
    		 Proportion with no evidence of macular oedema on OCT - 100 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    133
    130
    133
    Units: Percentage
    41
    45
    27
    Attachments
    		 Untitled (Filename: OCT anatomical outcomes for macula oedema.pdf)
    No statistical analyses for this end point

    Secondary: Proportion with no evidence of sub retinal detachment on OCT - 100 weeks

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    End point title
    		 Proportion with no evidence of sub retinal detachment on OCT - 100 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    133
    130
    133
    Units: percentage
    89
    85
    85
    Attachments
    		 Untitled (Filename: OCT anatomical outcomes for macula oedema.pdf)
    No statistical analyses for this end point

    Secondary: Cost effectiveness outcomes

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    End point title
    		 Cost effectiveness outcomes
    End point description
    The cost-effectiveness analysis found that bevacizumab was the most cost-effective intervention compared with licensed agents (ranibizumab and aflibercept). In the treatment of MO due to CRVO The model-based and within-trial analyses found small differences between the QALYs generated by aflibercept, ranibizumab and bevacizumab, but that bevacizumab led to substantially lower costs. The finding that bevacizumab was the most cost-effective intervention was robust to scenario analyses varying assumptions and data inputs.
    End point type
    Secondary
    End point timeframe
    100 weeks
    End point values
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Number of subjects analysed
    154
    154
    154
    Units: GBP
        arithmetic mean (standard deviation)
    11727 ± 2900
    10893 ± 2848
    6227 ± 2700
    Attachments
    		 Untitled (Filename: Table- cost effectiveness.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    100 weeks
    Adverse event reporting additional description
    MHRA definitions of adverse and serious adverse events were adopted. Adverse events were reported in an adverse events log in the eCRF. SAEs, SARs & SUSARs were recorded on an SAE form and reported to the Chief Investigator/delegate within 24 hours of learning of the occurrence. 2 pregnancies reported - 1 patient, 1 spouse - normal neonates.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0.0
    Reporting groups
    Reporting group title
    Ranibizumab arm
    Reporting group description
    		 -

    Reporting group title
    Aflibercept arm
    Reporting group description
    		 -

    Reporting group title
    Bevacizumab arm
    Reporting group description
    		 -

    Serious adverse events
    		 Ranibizumab arm Aflibercept arm Bevacizumab arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 155 (18.06%)
    41 / 154 (26.62%)
    30 / 154 (19.48%)
         number of deaths (all causes)
    3
    6
    4
         number of deaths resulting from adverse events
    2
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasias
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Other events
         subjects affected / exposed
    3 / 155 (1.94%)
    3 / 154 (1.95%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Immune system disorders
    Allergies
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorders
         subjects affected / exposed
    3 / 155 (1.94%)
    6 / 154 (3.90%)
    9 / 154 (5.84%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiovascular – vascular deaths
         subjects affected / exposed
    2 / 155 (1.29%)
    2 / 154 (1.30%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    2 / 2
    0 / 1
    Cardiovascular – non fatal MI
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular – non fatal stroke
         subjects affected / exposed
    2 / 155 (1.29%)
    4 / 154 (2.60%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular - other
         subjects affected / exposed
    7 / 155 (4.52%)
    14 / 154 (9.09%)
    8 / 154 (5.19%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 14
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Neurological disorders
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 154 (1.30%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hematological disorders
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Ear nose and throat disorders
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         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
    Other ophthalmological disorders
         subjects affected / exposed
    2 / 155 (1.29%)
    2 / 154 (1.30%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious endophthalmitis
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Retinal detachment
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal events
         subjects affected / exposed
    7 / 155 (4.52%)
    8 / 154 (5.19%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic disorders
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatological disorders
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 154 (1.30%)
    0 / 154 (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
    Renal and urinary disorders
    Genitourinary disorders
         subjects affected / exposed
    2 / 155 (1.29%)
    7 / 154 (4.55%)
    4 / 154 (2.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine disorder
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorders
         subjects affected / exposed
    1 / 155 (0.65%)
    4 / 154 (2.60%)
    5 / 154 (3.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
         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 arm Aflibercept arm Bevacizumab arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 155 (16.13%)
    24 / 154 (15.58%)
    27 / 154 (17.53%)
    Eye disorders
    Conversion to ischaemic CRVO
         subjects affected / exposed
    8 / 155 (5.16%)
    10 / 154 (6.49%)
    7 / 154 (4.55%)
         occurrences all number
    8
    10
    7
    Anterior segment neovascularisation
         subjects affected / exposed
    5 / 155 (3.23%)
    5 / 154 (3.25%)
    3 / 154 (1.95%)
         occurrences all number
    5
    5
    3
    Retinal Neovascularization
         subjects affected / exposed
    1 / 155 (0.65%)
    4 / 154 (2.60%)
    1 / 154 (0.65%)
         occurrences all number
    1
    4
    1
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 154 (1.30%)
    4 / 154 (2.60%)
         occurrences all number
    0
    2
    4
    IOP elevation
         subjects affected / exposed
    13 / 155 (8.39%)
    9 / 154 (5.84%)
    5 / 154 (3.25%)
         occurrences all number
    13
    9
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Sep 2014
    Changes to protocol and PIS - to cover MHRA grounds for non-acceptance Protocol and PIS: Changes to ensure patients use contraception for 6 months after their last intravitreal injection of anti-VEGF therapy Protocol: Changes to exclusion criteria
    27 Feb 2015
    Changes to protocol, PIS and ICF. Protocol: Changes to inclusion and exclusion criteria; treatment allocation guess form; retreatment criteria; criteria for restarting therapy; management of ischemic CRVO, neovascular glaucoma, angle or iris neovascularisation; expectedness; secondary outcome. PIS: To reflect that VA will form part of the routine eye exam; guidance on contraception ICF: To reflect new PIS
    16 Mar 2015
    New PI at existing site; removal of site; addition of new site. PIS: Amended following review of new SPCs; allows sites to use nurse injectors ICF: To reflect new PIS
    02 Jun 2015
    Adding new sites
    04 Aug 2015
    Adding new sites New PI at existing sites
    16 May 2016
    Changes to protocol; PIS; ICF Protocol: Changes to inclusion and exclusion criteria; rescreening; injectors; statistical changes; miscellaneous PIS: Changes to clarify who performs the injections; who prescribes antibiotic drops ICF: To reflect new PIS
    11 Aug 2016
    New PI at existing site
    20 Jun 2017
    New PI at existing site
    22 Aug 2017
    Change of SPC regarding Reference Safety Information
    16 Jul 2018
    New PI at existing site
    04 Sep 2018
    New PI at existing site

    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.
    The study may have enrolled eyes with limited potential for visual improvement (severe CRVO and poor perfusion or good acuity and thus a ceiling effect) Aflibercept was unlicensed at trial commencement - comparisons with Bevacizumab were post hoc.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31465100
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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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