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    Clinical Trial Results:
    Clinical Efficacy and Mechanistic Evaluation of Aflibercept for Proliferative Diabetic Retinopathy

    Summary
    EudraCT number
    		 2013-003272-12
    Trial protocol
    		 GB  
    Global end of trial date
    21 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2019
    First version publication date
    23 May 2019
    Other versions
    Summary report(s)
    		 End of Study Summary Report

    Trial information

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    Trial identification
    Sponsor protocol code
    SIVS1012
    Additional study identifiers
    ISRCTN number
    		 ISRCTN32207582
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Moorfields Eye Hospital
    Sponsor organisation address
    162 City Road, London, United Kingdom, EC1V 2PD
    Public contact
    Tania West, Moorfields Eye Hospital, 0044 020 7253 3411 x2937 , tania.west2@nhs.net
    Scientific contact
    Tania West, Moorfields Eye Hospital, 0044 020 7253 3411 x2937 , tania.west2@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
    17 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether mean change in best corrected visual acuity following intravitreal aflibercept therapy is non-inferior to panretinal photocoagulation (PRP) in eyes with proliferative diabetic retinopathy (PDR) at 52 weeks as measured by ETDRS letters.
    Protection of trial subjects
    Laser arm (comparator arm) is the standard of care for the last 40 years. Aflibercept (intervention arm) is licensed for other intraocular conditions. We sent the development safety update report (DSUR) annually to MHRA, ethics committee, sponsor and Bayer Patient and public involvement (PPI) were involved in the development of patient information sheet (PIS)
    Background therapy
    		 None for this trial
    Evidence for comparator
    		 Laser photocoagulation has been the mainstay of treatment for diabetic macular oedema and proliferative diabetic retinopathy for over 40 years based on robust evidence base. For proliferative diabetic retinopathy, the laser treatment (panretinal photocoagulation) is applied to the peripheral retinal tissue to destroy the peripheral photoreceptors and retinal pigment epithelium to reduce retinal oxygen consumption. This reduction in hypoxic drive results in decreased growth factor production especially VEGF, which in turn causes retinal new vessel regression. Response to laser varies, while it is most desirable to see a regression of new vessels, partial regression with no further growth may also result. Although timely laser treatment is very effective in reducing visual loss compared to no treatment, laser treatments a destructive procedure with well-documented side effects. Approximately 13% develop visual loss due to development or worsening of pre-existing macular oedema. In addition, it may lead to transient or permanent loss of visual function, including peripheral visual field defects, night vision loss, loss of contrast sensitivity, and progression of visual loss in nearly 5% of individuals despite appropriate treatment.
    Actual start date of recruitment
    22 Aug 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: 232
    Worldwide total number of subjects
    232
    EEA total number of subjects
    232
    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)
    188
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at the following 22 National Health Service clinical sites. We recruited 232 participants (116 per group) between Aug 22, 2014 and Nov 30, 2015.

    Pre-assignment
    Screening details
    		 Patients were identified from medical retina clinics and laser databases and contacted using an invitation letter with a pre-screening visit if required. 290 patients were assessed for eligibility. 58 excluded of which 51 eligibility criteria not met, 4 withdrawal of consent, 1 unable to come to study visits, 1 patient non compliant, 1 other

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    Research optometrists are the primary outcome assessors and were masked to treatment allocation. Visual fields and OCT technicians were also masked. Independent reading centre graders were masked to allocation of treatment. Investigators and patients were not masked

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Panretinal photocoagulation arm
    Arm description
    		 PRP is the current standard of care and was delivered as per routine clinical practice. Naïve PDR patients requiring PRP treatment were for the first time initiated on it and completed in fractionated 2 weekly sessions up to and may include week 4 and then reviewed at week 12. Participants with persistent active new vessels that had PRP previously and were randomized to the PRP arm received fill-in PRP in 1-2 two-weekly sessions. From week 12, all patients in the PRP arm were assessed for treatment response every 8 weeks and categorised exactly as the aflibercept arm Retreatment was based on regression pattern of the new vessels
    Arm type
    		 PRP

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Aflibercept arm
    Arm description
    		 All study eyes randomised to receive aflibercept received an intravitreal injection of aflibercept 2 mg/0.05ml at baseline, 4 and 8 weeks. Regression patterns of retinal neovascularisation were assessed using 4-field or wide angle fundus photography. Further treatment at week 12 was determined by the degree of regression of neovascularisation of disc and elsewhere on clinical examination with adequate visualisation of entire retina and compared to 7-field colour or wide-field photographs at screening. The patients were categorised according to treatment response into three groups: (1) No regression (2) Partial regression and (3) Total regression
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2 mg in 0.05 ml intravitreal administration

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Only the optometrists, technicians and reading centre graders were blinded for treatment allocation while doing assessments of outcomes
    Number of subjects in period 1
    		Panretinal photocoagulation arm Aflibercept arm
    Started
    116
    116
    Completed
    104
    107
    Not completed
    12
    9
         Adverse event, serious fatal
    1
    2
         Consent withdrawn by subject
    5
    5
         Lost to follow-up
    4
    2
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Panretinal photocoagulation arm
    Reporting group description
    		 PRP is the current standard of care and was delivered as per routine clinical practice. Naïve PDR patients requiring PRP treatment were for the first time initiated on it and completed in fractionated 2 weekly sessions up to and may include week 4 and then reviewed at week 12. Participants with persistent active new vessels that had PRP previously and were randomized to the PRP arm received fill-in PRP in 1-2 two-weekly sessions. From week 12, all patients in the PRP arm were assessed for treatment response every 8 weeks and categorised exactly as the aflibercept arm Retreatment was based on regression pattern of the new vessels

    Reporting group title
    Aflibercept arm
    Reporting group description
    		 All study eyes randomised to receive aflibercept received an intravitreal injection of aflibercept 2 mg/0.05ml at baseline, 4 and 8 weeks. Regression patterns of retinal neovascularisation were assessed using 4-field or wide angle fundus photography. Further treatment at week 12 was determined by the degree of regression of neovascularisation of disc and elsewhere on clinical examination with adequate visualisation of entire retina and compared to 7-field colour or wide-field photographs at screening. The patients were categorised according to treatment response into three groups: (1) No regression (2) Partial regression and (3) Total regression

    Reporting group values
    		 Panretinal photocoagulation arm Aflibercept arm Total
    Number of subjects
    		 116 116 232
    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)
    		 50.8 ( 13.2 ) 51.5 ( 14.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 44 33 77
        Male
    		 72 83 155
    Best corrected visual acuity
    Units: Subjects
        54 - 69
    		 11 10 21
        >= 70
    		 105 106 211
    Macular Oedema
    Units: Subjects
        No macular oedema
    		 87 87 174
        Non-central macular oedema
    		 28 28 56
        Central macular oedema
    		 1 1 2
    Central subfield thickness
    Units: microns
        arithmetic mean (standard deviation)
    		 271.6 ( 28.1 ) 275.3 ( 30.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Panretinal photocoagulation arm
    Reporting group description
    		 PRP is the current standard of care and was delivered as per routine clinical practice. Naïve PDR patients requiring PRP treatment were for the first time initiated on it and completed in fractionated 2 weekly sessions up to and may include week 4 and then reviewed at week 12. Participants with persistent active new vessels that had PRP previously and were randomized to the PRP arm received fill-in PRP in 1-2 two-weekly sessions. From week 12, all patients in the PRP arm were assessed for treatment response every 8 weeks and categorised exactly as the aflibercept arm Retreatment was based on regression pattern of the new vessels

    Reporting group title
    Aflibercept arm
    Reporting group description
    		 All study eyes randomised to receive aflibercept received an intravitreal injection of aflibercept 2 mg/0.05ml at baseline, 4 and 8 weeks. Regression patterns of retinal neovascularisation were assessed using 4-field or wide angle fundus photography. Further treatment at week 12 was determined by the degree of regression of neovascularisation of disc and elsewhere on clinical examination with adequate visualisation of entire retina and compared to 7-field colour or wide-field photographs at screening. The patients were categorised according to treatment response into three groups: (1) No regression (2) Partial regression and (3) Total regression

    Primary: Change in best corrected visual acuity ITT analysis

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    End point title
    		 Change in best corrected visual acuity ITT analysis [1]
    End point description
    End point type
    Primary
    End point timeframe
    52 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: It was an intention to treat analysis using linear mixed model
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    104
    105
    Units: ETDRS Letters
        arithmetic mean (standard error)
    -3.0 ( 0.7 )
    1.1 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Change in uniocular Esterman visual fields defects

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    End point title
    		 Change in uniocular Esterman visual fields defects
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    100
    99
    Units: ETDRS letters
        arithmetic mean (standard error)
    3.9 ( 0.9 )
    1.9 ( 0.8 )
    No statistical analyses for this end point

    Secondary: Change in binocular Esterman visual fields defects

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    End point title
    		 Change in binocular Esterman visual fields defects
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    102
    102
    Units: ETDRS letters
        arithmetic mean (standard error)
    3.2 ( 0.8 )
    0.2 ( 0.8 )
    No statistical analyses for this end point

    Secondary: Change in binocular visual acuity

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    End point title
    		 Change in binocular visual acuity
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    104
    106
    Units: ETDRS letters
        arithmetic mean (standard error)
    -1.8 ( 0.6 )
    0.5 ( 0.5 )
    No statistical analyses for this end point

    Secondary: Change in low luminance visual acuity

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    End point title
    		 Change in low luminance visual acuity
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    103
    107
    Units: ETDRS Letters
        arithmetic mean (standard error)
    -3.4 ( 1.0 )
    -1.5 ( 1.1 )
    No statistical analyses for this end point

    Secondary: Change in contrast sensitivity

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    End point title
    		 Change in contrast sensitivity
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    103
    107
    Units: ETDRS letters
        arithmetic mean (standard error)
    -1.0 ( 0.5 )
    -0.5 ( 0.5 )
    No statistical analyses for this end point

    Secondary: Change in VFQ 25 composite score

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    End point title
    		 Change in VFQ 25 composite score
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    103
    104
    Units: score
        arithmetic mean (standard error)
    -1.8 ( 1.3 )
    -0.1 ( 1.2 )
    No statistical analyses for this end point

    Secondary: Change in RetDQoL impact score

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    End point title
    		 Change in RetDQoL impact score
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    99
    103
    Units: score
        arithmetic mean (standard error)
    0.2 ( 0.2 )
    0.0 ( 0.2 )
    No statistical analyses for this end point

    Secondary: Change in RetTSQ total score

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    End point title
    		 Change in RetTSQ total score
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    100
    103
    Units: score
        arithmetic mean (standard error)
    1.8 ( 1.0 )
    5.5 ( 1.3 )
    No statistical analyses for this end point

    Secondary: Change in central subfield thickness

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    End point title
    		 Change in central subfield thickness
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    103
    106
    Units: microns
        arithmetic mean (standard error)
    24.0 ( 5.5 )
    -8.9 ( 2.3 )
    No statistical analyses for this end point

    Secondary: Regression pattern

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    End point title
    		 Regression pattern
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    105
    110
    Units: Subjects
        Total regression
    25
    81
        Partial regression
    58
    28
        No regression
    22
    1
    No statistical analyses for this end point

    Secondary: Regression pattern

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    End point title
    		 Regression pattern
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    104
    107
    Units: Subjects
        Total regression
    35
    68
        Partial regression
    46
    18
        No regression
    7
    2
        Reactivation
    16
    19
    No statistical analyses for this end point

    Secondary: Change in diabetic retinopathy score levels

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    End point title
    		 Change in diabetic retinopathy score levels
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    99
    97
    Units: Subjects
        Worse than or = Level 61
    86
    69
        Improved to Level 53 or better
    13
    28
        Improved to Level 47 or better
    6
    17
        Improved to Level 43 or better
    6
    17
    No statistical analyses for this end point

    Secondary: Change in diabetic retinopathy score levels

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    End point title
    		 Change in diabetic retinopathy score levels
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Panretinal photocoagulation arm Aflibercept arm
    Number of subjects analysed
    102
    104
    Units: Subjects
        Worse than or = Level 61
    92
    81
        Improved to Level 53 or better
    10
    23
        Improved to Level 47 or better
    2
    6
        Improved to Level 43 or better
    2
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    August 2014 to December 2016
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 no dictionary used
    Dictionary version
    0.0
    Reporting groups
    Reporting group title
    Panretinal photocoagulation arm
    Reporting group description
    		 PRP is the current standard of care and was delivered as per routine clinical practice. Naïve PDR patients requiring PRP treatment were for the first time initiated on it and completed in fractionated 2 weekly sessions up to and may include week 4 and then reviewed at week 12. Participants with persistent active new vessels that had PRP previously and were randomized to the PRP arm received fill-in PRP in 1-2 two-weekly sessions. From week 12, all patients in the PRP arm were assessed for treatment response every 8 weeks and categorised exactly as the aflibercept arm Retreatment was based on regression pattern of the new vessels

    Reporting group title
    Aflibercept arm
    Reporting group description
    		 All study eyes randomised to receive aflibercept received an intravitreal injection of aflibercept 2 mg/0.05ml at baseline, 4 and 8 weeks. Regression patterns of retinal neovascularisation were assessed using 4-field or wide angle fundus photography. Further treatment at week 12 was determined by the degree of regression of neovascularisation of disc and elsewhere on clinical examination with adequate visualisation of entire retina and compared to 7-field colour or wide-field photographs at screening. The patients were categorised according to treatment response into three groups: (1) No regression (2) Partial regression and (3) Total regression

    Serious adverse events
    		 Panretinal photocoagulation arm Aflibercept arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 116 (25.86%)
    30 / 116 (25.86%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    1
    2
    General disorders and administration site conditions
    Other
    Additional description: viral infection, pregnant lady - IUGR taken for caesarean
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory
    Additional description: Chest infection, shortness of breath, left lower lobe pneumonia, viral pneumonia, bronchopneumonia, pulmonary embolism, pneumonia
         subjects affected / exposed
    5 / 116 (4.31%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric
    Additional description: excess alcohol intake, overdose of citalopram, overdose of insulin, cocaine, zopliclone, temazepam
         subjects affected / exposed
    0 / 116 (0.00%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiovascular
    Additional description: Chest pain, stroke, acute cardiac failure, heart failure, pulmonary oedema, shortness of breath, non ST elevation MI, possible TIA, coronary artery disease, unstable angina, myocardial infarction
         subjects affected / exposed
    4 / 116 (3.45%)
    7 / 116 (6.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Nervous system disorders
    Neurological
    Additional description: fall, unresponsive
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haematological
    Additional description: Chronic myeloid leukaemia. multiple myeloma
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    New or increase in severity of vitreous haemorrhage
         subjects affected / exposed
    9 / 116 (7.76%)
    4 / 116 (3.45%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal ulcer
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrovascular proliferation
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    reduced blurred vision
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastro-intestinal
    Additional description: abdominal pain, perforated stomach ulcer, vomiting, diarrhoea, constipation, nausea, pain, gastroenteritis, exacerbation of gastroparesis
         subjects affected / exposed
    2 / 116 (1.72%)
    6 / 116 (5.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Transaminitis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatological
    Additional description: gout, wide excision of squamous cell carcinoma, cellulitis, open wound on knee
         subjects affected / exposed
    2 / 116 (1.72%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Genitourinary
    Additional description: renal biopsy, pre-malignant endometrial lesion, acute renal failure, frequency of micturition, loin pain, acute pyelonephritis, urinary tract infection
         subjects affected / exposed
    3 / 116 (2.59%)
    4 / 116 (3.45%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine disorder
    Additional description: hyperglycaemia, diabetic ketoacidosis, low glucose level, uncontrolled diabetes, kidney and pancreas transplant, hypoglycaemic attack
         subjects affected / exposed
    3 / 116 (2.59%)
    5 / 116 (4.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal
         subjects affected / exposed
    5 / 116 (4.31%)
    6 / 116 (5.17%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Panretinal photocoagulation arm Aflibercept arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 116 (62.07%)
    83 / 116 (71.55%)
    General disorders and administration site conditions
    Allergies
    Additional description: Hayfever, allergic reaction to fluorescein
         subjects affected / exposed
    3 / 116 (2.59%)
    4 / 116 (3.45%)
         occurrences all number
    3
    4
    Other
    Additional description: Flu, raised creatinine, fatigue, dental abscess, cold, blunt trauma, cut over eyebrow, infection foot, generalised weakness, viral cold, fall
         subjects affected / exposed
    8 / 116 (6.90%)
    9 / 116 (7.76%)
         occurrences all number
    10
    12
    Immune system disorders
    Rheumatoid arthritis
    Additional description: both hands
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory
    Additional description: cough, runny nose, flu, chest infection , URTI, common cold, shortness of breath, dyspnoea, sore throat, pleural effusion
         subjects affected / exposed
    15 / 116 (12.93%)
    20 / 116 (17.24%)
         occurrences all number
    16
    23
    Psychiatric disorders
    Psychiatric
    Additional description: anxiety, depression, self harm
         subjects affected / exposed
    2 / 116 (1.72%)
    2 / 116 (1.72%)
         occurrences all number
    2
    2
    Cardiac disorders
    Cardiovascular events
    Additional description: TIA, non ST MI, chest pain, hypertension, hypotension, left ventricular hypertrophy, dizziness,
         subjects affected / exposed
    5 / 116 (4.31%)
    9 / 116 (7.76%)
         occurrences all number
    6
    10
    Nervous system disorders
    Neurological
    Additional description: migraine, epilepsy, vertigo, memory loss, restless leg, headache, blurred vision, carpal tunnel syndrome
         subjects affected / exposed
    4 / 116 (3.45%)
    6 / 116 (5.17%)
         occurrences all number
    4
    8
    Blood and lymphatic system disorders
    Haematological
    Additional description: anaemia, hyperkalaemia, low Hb levels, gum bleeding
         subjects affected / exposed
    2 / 116 (1.72%)
    4 / 116 (3.45%)
         occurrences all number
    2
    4
    Ear and labyrinth disorders
    Ear Nose and Throat
    Additional description: sinusitis, ear infection, labyrinthitis, tooth cavity infection, hearing loss, flu, sore throat, laryngitis, glandular fever, tonsillitis,
         subjects affected / exposed
    8 / 116 (6.90%)
    8 / 116 (6.90%)
         occurrences all number
    10
    9
    Eye disorders
    Cataract progression
         subjects affected / exposed
    1 / 116 (0.86%)
    2 / 116 (1.72%)
         occurrences all number
    2
    2
    New or progressing tractional RD
         subjects affected / exposed
    2 / 116 (1.72%)
    1 / 116 (0.86%)
         occurrences all number
    2
    1
    New or increase in severity of vitreous haemorrhage
         subjects affected / exposed
    22 / 116 (18.97%)
    14 / 116 (12.07%)
         occurrences all number
    27
    21
    Macular Oedema
         subjects affected / exposed
    2 / 116 (1.72%)
    4 / 116 (3.45%)
         occurrences all number
    2
    4
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 116 (0.86%)
    7 / 116 (6.03%)
         occurrences all number
    1
    7
    Eye pain
         subjects affected / exposed
    4 / 116 (3.45%)
    4 / 116 (3.45%)
         occurrences all number
    5
    4
    Transient reduced visual acuity
         subjects affected / exposed
    8 / 116 (6.90%)
    2 / 116 (1.72%)
         occurrences all number
    9
    2
    Raised intraocular pressure
         subjects affected / exposed
    1 / 116 (0.86%)
    2 / 116 (1.72%)
         occurrences all number
    1
    2
    Other
    Additional description: NVE fellow eye, floaters, blurred vision, uveitis, corneal abrasion, hordeolum, lamellar hole, ERM, inflammation of tear gland, blepharitis, herpes simplex keratitis, superficial punctate keratitis, nystagmus
         subjects affected / exposed
    18 / 116 (15.52%)
    24 / 116 (20.69%)
         occurrences all number
    25
    37
    Gastrointestinal disorders
    GI group of disorders
    Additional description: vomiting, gastric reflux, irritable bowel syndrome, sickness, gastroenteritis, diarrhoea, heart burn, faecal impaction, oesophagitis, constipation
         subjects affected / exposed
    7 / 116 (6.03%)
    9 / 116 (7.76%)
         occurrences all number
    7
    10
    Skin and subcutaneous tissue disorders
    Dermatological
    Additional description: diabetic foot ulcer, infected breast cyst, stomach abscess drained, boils, suspected skin cancer, cellulitis, itching, blister, infected sebaceous cyst
         subjects affected / exposed
    5 / 116 (4.31%)
    8 / 116 (6.90%)
         occurrences all number
    5
    8
    Renal and urinary disorders
    Genito urinary disorders
    Additional description: poor renal function, vaginal discharge, UTI, chronic renal failure, epididymo-orchitis, renal colic,
         subjects affected / exposed
    5 / 116 (4.31%)
    9 / 116 (7.76%)
         occurrences all number
    8
    9
    Endocrine disorders
    All endocrine disorders
    Additional description: hypoglycaemic episode, dehydration, unstable diabetes, Vit D deficiency
         subjects affected / exposed
    6 / 116 (5.17%)
    5 / 116 (4.31%)
         occurrences all number
    6
    6
    Increasing severity of diabetic retinopathy
         subjects affected / exposed
    1 / 116 (0.86%)
    5 / 116 (4.31%)
         occurrences all number
    1
    5
    Musculoskeletal and connective tissue disorders
    Musculo-skeletal
    Additional description: generalised aches and pains, swollen painful foot, tendinitis, fracture toes, headache, fall, pulled muscle, ulcer toe, knee pain, trigger finger, carpal tunnel syndrome, myalgia, back pain, damaged ligaments, cellulitis, restless leg syndrome
         subjects affected / exposed
    17 / 116 (14.66%)
    17 / 116 (14.66%)
         occurrences all number
    24
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2014
    Labelling of IMP
    10 Oct 2014
    Letter of invitation, patient consent form, patient information sheet revision and addition of 5 sites
    17 Sep 2015
    Inclusion of qualified trained nurse injectors

    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.
    It was a phase 2b study with follow-up for only 52 weeks. As a 5 year study, it will provide long-term outcomes of ranibizumab in PDR, information about the disease-modifying effect of anti-VEGF, and the long-term compliance of patients.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30303670
    http://www.ncbi.nlm.nih.gov/pubmed/28494920
    For support, Contact us.
    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
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