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    Clinical Trial Results:
    A randomised control trial of alternative treatments to Inhibit VEGf in Age-related choroidal Neovascularisation (IVAN)

    Summary
    EudraCT number
    2007-001281-33
    Trial protocol
    GB  
    Global end of trial date
    31 Dec 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Mar 2020
    First version publication date
    31 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RGHT000449
    Additional study identifiers
    ISRCTN number
    ISRCTN92166560
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Belfast Health and Social Care Trust
    Sponsor organisation address
    Research Office, 2nd Floor King Edward Building, Royal Hospitals, Grosvenor Road, Belfast, United Kingdom, BT12 6BA
    Public contact
    Research Office, Belfast Health and Social Care Trust, Research.Office@belfasttrust.hscni.net
    Scientific contact
    Research Office, Belfast Health and Social Care Trust, Research.Office@belfasttrust.hscni.net
    Sponsor organisation name
    Queen's University Belfast
    Sponsor organisation address
    Research Governance, Ethics and Integrity, Queen’s University Belfast, 63 University Road, Belfast, United Kingdom, BT7 1NN
    Public contact
    Research Governance, Queen's University Belfast, researchgovernance@qub.ac.uk
    Scientific contact
    Research Governance, Queen's University Belfast, researchgovernance@qub.ac.uk
    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
    24 Apr 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Nov 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the relative effectiveness of two vascular endothelial growth factor (VEGF) inhibitors, i.e. Lucentis® (ranibizumab) and Avastin® (bevacizumab), delivered into the eye by intravitreal injection on visual outcome in patients with choroidal neovascularisation (CNV) from age−related macular degeneration (AMD). To estimate the effectiveness of more frequent (continuous) versus less frequent (discontinuous) VEGF administration in improving or maintaining visual function, with stringent criteria for restarting treatment to prevent visual acuity loss in patients receiving less frequent treatment.
    Protection of trial subjects
    All potential participants were sent or given an invitation letter and patient information leaflet (PIL) (approved by a NHS research ethics committee) describing the study. All participants had time to read the PIL and to discuss their participation with others outside the research team (e.g. relatives or friends) if they wished. Participants had a minimum of 48 hours to decide whether they wished to take part. A member of research staff was available to answer questions that patients may have about the trial. The PIL included a phone number that patients can telephone to obtain more information. All members of the direct healthcare team are contractually bound to abide by standard NHS conditions of confidentiality. All of the clinical staff at the study sites will have attended appropriate courses on GCP and will be familiar with issues concerning informed consent. A member of research staff asked the patient whether he/she has understood the information about the trial, and whether he/she had any more questions before asking the patient if he/she was willing to take part in the trial. Written informed consent was obtained for every trial participant.
    Background therapy
    Wet or neovascular macular degeneration is a condition which causes severe sight loss in older people. Until recently, available treatments only slowed down the rate of sight loss with most patients becoming moderately or severely visually impaired despite optimal management. A drug known as Lucentis (Ranibizumab) was found to prevent further sight loss in over 90% of those treated. The treatment involved injection of the drug every 4 weeks into the vitreous jelly of the eye for up to two years. A very similar drug, Avastin (Bevacizumab), but which is much cheaper, also appears to have the same benefits but it had not been tested in randomised controlled trials.
    Evidence for comparator
    Intravitreal treatment with ranibizumab, an anti body to vascular endothelial growth factor (VEGF), was shown to be effective in neovascular age related macular degeneration compared with photodynamic therapy or no treatment. Anti-VEGF drugs were thus established as a standard of care for neovascular age-related macular degeneration. Bevacizumab, an antibody to VEGF that is licensed for treatment of bowel cancers, is the parent molecule from which ranibizumab was developed. Small non-randomised studies done while ranibizumab was awaiting marketing authorisation suggested that bevacizumab had similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. These findings were important, because every dose of ranibizumab is expensive and treatment can be needed every month for several years. There were concerns about possible side effects of both drugs, which had not been directly compared. There is also very little evidence on which to base criteria for stopping treatment and so considerable uncertainty about precisely how much treatment might cost in the longer term; this is a major concern to the NHS, not just because of the drug costs but also because of the costs involved in regular monthly treatment. The absence of robust information about the safety of bevacizumab in the treatment of neovascular age-related macular degeneration and uncertainty about treatment frequency for both bevacizumab and ranibizumab led us to undertake the Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial in the UK. The IVAN trial was designed to compare the clinical efficacy of the two drugs and to compare a reduced treatment regimen versus two years of continuous treatment.
    Actual start date of recruitment
    27 Mar 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Scientific research
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 610
    Worldwide total number of subjects
    610
    EEA total number of subjects
    610
    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)
    27
    From 65 to 84 years
    447
    85 years and over
    136

    Subject disposition

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    Recruitment
    Recruitment details
    Between 27 March 2008 and 15 October 2010, 2, 693 patients were screened for inclusion in the trial and full informed consent was taken from 610 patients who agreed to take part in the study. All potential participants received an information leaflet.

    Pre-assignment
    Screening details
    Of the 693 patients screened for inclusion in the trial, 28 were identified as ineligible and 37 excluded for other reasons. The remaining 628 patients were randomised into the trial. Five of these 628 participants were randomised in error and a further 13 were not treated, leaving 610 who recieved the study drugs and were included in the analyses.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Carer, Assessor, Subject
    Blinding implementation details
    Allocations were computer generated and concealed with an internet-based system (Sealed Envelope, London, UK). Study participants and clinical assessors (nurses, optometrists, imaging technicians, and clinicians) were masked to drug allocation. Study drugs were dispensed by pharmacy staff who were unmasked, but had no other role in the study. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point both investigator and participant were unmasked.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Ranibizumab
    Arm description
    Intravitreal injections of ranibizumab (0.5mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).
    Arm type
    Active comparator

    Investigational medicinal product name
    Lucentis
    Investigational medicinal product code
    Other name
    Ranibizumab
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Administration: Intravitreal injections. Drug dose: 0·5 mg

    Arm title
    Bevacizumab
    Arm description
    Intravitreal injections of bevacizumab (1.25mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).
    Arm type
    Experimental

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Administration: Intravitreal injections. Drug dose: 1·25 mg

    Arm title
    Continuous
    Arm description
    Monthly treatment.
    Arm type
    Continuous treatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Discontinuous
    Arm description
    Treated if pre specified clinical and OCT criteria for active disease were met. If re-treatment was needed, a further cycle of three doses was given monthly.
    Arm type
    Discontinuous treatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Ranibizumab Bevacizumab Continuous Discontinuous
    Started
    314
    296
    308
    302
    Completed
    314
    296
    308
    302

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ranibizumab
    Reporting group description
    Intravitreal injections of ranibizumab (0.5mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

    Reporting group title
    Bevacizumab
    Reporting group description
    Intravitreal injections of bevacizumab (1.25mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

    Reporting group title
    Continuous
    Reporting group description
    Monthly treatment.

    Reporting group title
    Discontinuous
    Reporting group description
    Treated if pre specified clinical and OCT criteria for active disease were met. If re-treatment was needed, a further cycle of three doses was given monthly.

    Reporting group values
    Ranibizumab Bevacizumab Continuous Discontinuous Total
    Number of subjects
    314 296 308 302
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age at randomisation
    Units: years
        arithmetic mean (standard deviation)
    77.8 ± 7.6 77.7 ± 7.3 77.8 ± 8.0 77.6 ± 6.8 -
    Gender categorical
    Units: Subjects
        Female
    185 181 182 184 366
        Male
    129 115 126 118 244
    Angina
    Units: Subjects
        Yes
    35 51 45 41 86
        No
    279 245 263 261 524
    Dyspnoea
    Units: Subjects
        Yes
    57 60 57 60 117
        No
    256 235 249 242 491
        Missing
    1 1 2 0 2
    Myocardial Infarction
    Units: Subjects
        Yes
    24 22 26 20 46
        No
    290 274 282 282 564
    Transient ischaemic attack
    Units: Subjects
        Yes
    20 9 15 14 29
        No
    274 273 276 271 547
        Missing
    20 14 17 17 34
    Stroke
    Units: Subjects
        Yes
    7 7 4 10 14
        No
    307 288 304 291 595
        Missing
    0 1 0 1 1
    DVT/PE
    DVT/PE = Deep-vein thrombosis or pulmonary embolism.
    Units: Subjects
        Yes
    16 18 16 18 34
        No
    297 277 292 282 574
        Missing
    1 1 0 2 2
    Current or past smoker
    Units: Subjects
        Yes
    200 185 194 191 385
        No
    109 110 111 108 219
        Missing
    5 1 3 3 6
    Foveal centre involvement
    Units: Subjects
        Yes
    230 223 235 218 453
        No
    79 66 66 79 145
        Missing
    5 7 7 5 12
    Choroidal neovascularisation
    Units: Subjects
        Yes
    156 162 170 148 318
        No
    149 125 129 145 274
        Missing
    9 9 9 9 18
    Haemorrhage
    Units: Subjects
        Yes
    86 88 89 85 174
        No
    222 204 214 212 426
        Missing
    6 4 5 5 10
    Other foveal centre involvement
    Units: Subjects
        Yes
    47 30 39 38 77
        No
    259 262 262 259 521
        Missing
    8 4 7 5 12
    No choroidal neovascularisation or unable to grade
    Units: Subjects
        Yes
    7 8 4 11 15
        No
    302 286 300 288 588
        Missing
    5 2 4 3 7
    Geographic atrophy
    Units: Subjects
        Yes
    25 18 24 19 43
        No
    284 277 280 281 561
        Missing
    5 1 4 2 6
    Blood pressure (Systolic)
    Units: mmHg
        arithmetic mean (standard deviation)
    141.9 ± 19.5 143.0 ± 19.5 143.2 ± 19.8 141.7 ± 19.1 -
    Blood pressure (Diastolic)
    Units: mmHg
        arithmetic mean (standard deviation)
    76.4 ± 10.2 77.1 ± 9.9 77.4 ± 10.1 76.2 ± 10.0 -
    Best corrected visual acuity
    Units: Letters
        arithmetic mean (standard deviation)
    61.8 ± 15.0 61.1 ± 15.5 60.1 ± 15.5 62.9 ± 15.0 -
    Near visual acuity
    Data missing for 7 patients (3 Ranibizumab, 4 Bevacizumab; 5 Continuous, 2 Discontinuous)
    Units: logMAR
        arithmetic mean (standard deviation)
    0.66 ± 0.34 0.67 ± 0.33 0.70 ± 0.34 0.63 ± 0.32 -
    Belfast reading index
    Data missing for 34 patients (21 Ranibizumab, 13 Bevacizumab; 21 Continuous, 13 Discontinuous)
    Units: Index
        median (inter-quartile range (Q1-Q3))
    36.9 (15.6 to 65.3) 35.0 (14.0 to 69.6) 33.1 (13.6 to 67.7) 40.0 (16.3 to 69.6) -
    Contrast sensitivity
    Data missing for 3 patients (3 Ranibizumab, 0 Bevacizumab; 3 Continuous, 0 Discontinuous)
    Units: Letters
        arithmetic mean (standard deviation)
    26.2 ± 6.2 26.3 ± 5.7 26.1 ± 6.0 26.4 ± 5.9 -
    Total thickness at fovea
    Data missing for 53 patients (24 Ranibizumab, 29 Bevacizumab; 27 Continuous, 26 Discontinuous)
    Units: µm
        arithmetic mean (standard deviation)
    471.6 ± 192.5 465.6 ± 183.1 473.2 ± 187.9 464.1 ± 188.2 -
    Retinal plus subretinal fluid thickness at fovea
    Data missing for 53 patients (24 Ranibizumab, 29 Bevacizumab; 27 Continuous, 26 Discontinuous)
    Units: µm
        arithmetic mean (standard deviation)
    271.9 ± 128.6 264.0 ± 131.6 263.9 ± 126.9 272.4 ± 133.2 -
    Area of lesion, optic disc area
    Data missing for 23 patients (11 Ranibizumab, 12 Bevacizumab; 10 Continuous, 13 Discontinuous)
    Units: µm
        median (inter-quartile range (Q1-Q3))
    3.28 (1.10 to 7.76) 3.97 (1.42 to 8.24) 3.68 (1.27 to 7.81) 3.59 (1.16 to 8.42) -
    EQ-5D state score
    Data missing for 2 patients (1 Ranibizumab, 1 Bevacizumab; 0 Continuous, 2 Discontinuous)
    Units: Utility score
        median (inter-quartile range (Q1-Q3))
    0.81 (0.73 to 1.00) 0.85 (0.73 to 1.00) 0.85 (0.73 to 1.00) 0.85 (0.73 to 1.00) -

    End points

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    End points reporting groups
    Reporting group title
    Ranibizumab
    Reporting group description
    Intravitreal injections of ranibizumab (0.5mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

    Reporting group title
    Bevacizumab
    Reporting group description
    Intravitreal injections of bevacizumab (1.25mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

    Reporting group title
    Continuous
    Reporting group description
    Monthly treatment.

    Reporting group title
    Discontinuous
    Reporting group description
    Treated if pre specified clinical and OCT criteria for active disease were met. If re-treatment was needed, a further cycle of three doses was given monthly.

    Subject analysis set title
    Ranibizumab: Baseline BCVA in fellow eye ≥75
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Ranibizumab arm - Baseline BCVA in fellow eye ≥75

    Subject analysis set title
    Ranibizumab: Baseline BCVA in fellow eye <75
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Ranibizumab arm - Baseline BCVA in fellow eye <75

    Subject analysis set title
    Bevacizumab: Baseline BCVA in fellow eye ≥75
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Bevacizumab arm - Baseline BCVA in fellow eye ≥75

    Subject analysis set title
    Bevacizumab: Baseline BCVA in fellow eye <75
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Bevacizumab arm - Baseline BCVA in fellow eye <75

    Subject analysis set title
    Continuous: Baseline BCVA in fellow eye ≥75
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Continuous arm - Baseline BCVA in fellow eye ≥75

    Subject analysis set title
    Continuous: Baseline BCVA in fellow eye <75
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Continuous arm - Baseline BCVA in fellow eye <75

    Subject analysis set title
    Discontinuous: Baseline BCVA in fellow eye ≥75
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Discontinuous arm - Baseline BCVA in fellow eye ≥75

    Subject analysis set title
    Discontinuous: Baseline BCVA in fellow eye <75
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Discontinuous arm - Baseline BCVA in fellow eye <75

    Subject analysis set title
    Ranibizumab: Baseline BCVA <55
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Ranibizumab arm - Baseline BCVA in study eye <55

    Subject analysis set title
    Ranibizumab: Baseline BCVA ≥55
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Ranibizumab arm - Baseline BCVA in study eye ≥55

    Subject analysis set title
    Bevacizumab: Baseline BCVA <55
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Bevacizumab arm - Baseline BCVA in study eye <55

    Subject analysis set title
    Bevacizumab: Baseline BCVA ≥55
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Bevacizumab arm - Baseline BCVA in study eye ≥55

    Subject analysis set title
    Continuous: Baseline BCVA <55
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Continuous arm - Baseline BCVA in study eye <55

    Subject analysis set title
    Continuous: Baseline BCVA ≥55
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Continuous arm - Baseline BCVA in study eye ≥55

    Subject analysis set title
    Disontinuous: Baseline BCVA <55
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Discontinuous arm - Baseline BCVA in study eye <55

    Subject analysis set title
    Disontinuous: Baseline BCVA ≥55
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Discontinuous arm - Baseline BCVA in study eye ≥55

    Subject analysis set title
    Ranibizumab: Baseline CNV size <6mm
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Ranibizumab arm - Baseline CNV size <6mm

    Subject analysis set title
    Ranibizumab: Baseline CNV size ≥6mm
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Ranibizumab arm - Baseline CNV size ≥6mm

    Subject analysis set title
    Bevacizumab: Baseline CNV size <6mm
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Bevacizumab arm - Baseline CNV size <6mm

    Subject analysis set title
    Bevacizumab: Baseline CNV size ≥6mm
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Bevacizumab arm - Baseline CNV size ≥6mm

    Subject analysis set title
    Continuous arm: Baseline CNV size <6mm
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Continuous arm - Baseline CNV size <6mm

    Subject analysis set title
    Continuous arm: Baseline CNV size ≥6mm
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Continuous arm - Baseline CNV size ≥6mm

    Subject analysis set title
    Discontinuous arm: Baseline CNV size <6mm
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Discontinuous arm - Baseline CNV size <6mm

    Subject analysis set title
    Discontinuous arm: Baseline CNV size ≥6mm
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Discontinuous arm - Baseline CNV size ≥6mm

    Subject analysis set title
    Ranibizumab: Baseline lesion <50% CNV
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Ranibizumab arm - Baseline lesion <50% CNV

    Subject analysis set title
    Ranibizumab: Baseline lesion ≥50% CNV
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Ranibizumab arm - Baseline lesion ≥50% CNV

    Subject analysis set title
    Bevacizumab: Baseline lesion <50% CNV
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Bevacizumab arm - Baseline lesion <50% CNV

    Subject analysis set title
    Bevacizumab: Baseline lesion ≥50% CNV
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Bevacizumab arm - Baseline lesion ≥50% CNV

    Subject analysis set title
    Continuous: Baseline lesion <50% CNV
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Continuous arm - Baseline lesion <50% CNV

    Subject analysis set title
    Continuous: Baseline lesion ≥50% CNV
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Continuous arm - Baseline lesion ≥50% CNV

    Subject analysis set title
    Discontinuous: Baseline lesion <50% CNV
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Discontinuous arm - Baseline lesion <50% CNV

    Subject analysis set title
    Discontinuous: Baseline lesion ≥50% CNV
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Discontinuous arm - Baseline lesion ≥50% CNV

    Subject analysis set title
    Ranibizumab: Baseline RAP absent
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Ranibizumab arm - Baseline RAP absent

    Subject analysis set title
    Ranibizumab: Baseline RAP present
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Ranibizumab arm - Baseline RAP present

    Subject analysis set title
    Bevacizumab: Baseline RAP absent
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Bevacizumab arm - Baseline RAP absent

    Subject analysis set title
    Bevacizumab: Baseline RAP present
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Bevacizumab arm - Baseline RAP present

    Subject analysis set title
    Continuous: Baseline RAP absent
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Continuous arm - Baseline RAP absent

    Subject analysis set title
    Continuous: Baseline RAP present
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Continuous arm - Baseline RAP present

    Subject analysis set title
    Discontinuous: Baseline RAP absent
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Discontinuous arm - Baseline RAP absent

    Subject analysis set title
    Discontinuous: Baseline RAP present
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup: Discontinuous arm - Baseline RAP present

    Subject analysis set title
    Discontinuous bevacizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Analysis group for resource use and cost effectiveness: Discontinuous bevacizumab

    Subject analysis set title
    Continuous bevacizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Analysis group for resource use and cost effectiveness: Continuous bevacizumab

    Subject analysis set title
    Discontinuous ranibizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Analysis group for resource use and cost effectiveness: Discontinuous ranibizumab

    Subject analysis set title
    Continuous ranibizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Analysis group for resource use and cost effectiveness: Continuous ranibizumab

    Primary: Best corrected visual acuity

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    End point title
    Best corrected visual acuity
    End point description
    Best corrected visual acuity (BCVA) measured as the number of letters read on a standard Early Treatment Diabetic Retinopathy Study chart.
    End point type
    Primary
    End point timeframe
    Measured at 0, 3, 6, 9, 12, 15, 18, 21 and 24 months
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous Ranibizumab: Baseline BCVA in fellow eye ≥75 Ranibizumab: Baseline BCVA in fellow eye <75 Bevacizumab: Baseline BCVA in fellow eye ≥75 Bevacizumab: Baseline BCVA in fellow eye <75 Continuous: Baseline BCVA in fellow eye ≥75 Continuous: Baseline BCVA in fellow eye <75 Discontinuous: Baseline BCVA in fellow eye ≥75 Discontinuous: Baseline BCVA in fellow eye <75 Ranibizumab: Baseline BCVA <55 Ranibizumab: Baseline BCVA ≥55 Bevacizumab: Baseline BCVA <55 Bevacizumab: Baseline BCVA ≥55 Continuous: Baseline BCVA <55 Continuous: Baseline BCVA ≥55 Disontinuous: Baseline BCVA <55 Disontinuous: Baseline BCVA ≥55 Ranibizumab: Baseline CNV size <6mm Ranibizumab: Baseline CNV size ≥6mm Bevacizumab: Baseline CNV size <6mm Bevacizumab: Baseline CNV size ≥6mm Continuous arm: Baseline CNV size <6mm Continuous arm: Baseline CNV size ≥6mm Discontinuous arm: Baseline CNV size <6mm Discontinuous arm: Baseline CNV size ≥6mm Ranibizumab: Baseline lesion <50% CNV Ranibizumab: Baseline lesion ≥50% CNV Bevacizumab: Baseline lesion <50% CNV Bevacizumab: Baseline lesion ≥50% CNV Continuous: Baseline lesion <50% CNV Continuous: Baseline lesion ≥50% CNV Discontinuous: Baseline lesion <50% CNV Discontinuous: Baseline lesion ≥50% CNV Ranibizumab: Baseline RAP absent Ranibizumab: Baseline RAP present Bevacizumab: Baseline RAP absent Bevacizumab: Baseline RAP present Continuous: Baseline RAP absent Continuous: Baseline RAP present Discontinuous: Baseline RAP absent Discontinuous: Baseline RAP present
    Number of subjects analysed
    314
    296
    308
    302
    161
    145
    145
    142
    166
    135
    140
    152
    86
    228
    96
    200
    104
    204
    78
    224
    201
    102
    181
    103
    198
    100
    184
    105
    62
    224
    54
    213
    58
    227
    58
    210
    245
    43
    241
    31
    248
    38
    238
    36
    Units: Letters
        arithmetic mean (standard deviation)
    67.8 ± 17.0
    66.1 ± 18.4
    66.6 ± 17.9
    67.3 ± 17.5
    67.7 ± 18.1
    68.1 ± 15.9
    66.3 ± 17.3
    66.0 ± 19.6
    67.3 ± 17.6
    66.2 ± 18.1
    66.7 ± 17.8
    67.8 ± 17.5
    53.3 ± 18.0
    72.3 ± 13.8
    49.1 ± 18.3
    73.6 ± 12.6
    53.0 ± 19.0
    72.8 ± 13.4
    48.3 ± 16.9
    73.0 ± 13.2
    68.7 ± 15.9
    65.6 ± 19.0
    67.1 ± 17.6
    64.4 ± 19.6
    68.7 ± 16.0
    62.4 ± 20.4
    67.2 ± 17.4
    67.6 ± 17.8
    65.3 ± 18.5
    68.0 ± 16.9
    67.6 ± 17.9
    65.8 ± 18.6
    64.7 ± 17.7
    66.7 ± 18.1
    67.9 ± 18.6
    67.2 ± 17.5
    67.3 ± 17.2
    69.7 ± 16.2
    66.1 ± 18.1
    70.4 ± 17.3
    66.2 ± 17.8
    70.3 ± 16.4
    67.1 ± 17.5
    69.5 ± 16.9
    Statistical analysis title
    BCVA by drug
    Statistical analysis description
    Difference in BCVA at 2 years, by drug allocation. Difference is estimated using data from visits 0, 3, 6, 9, 12, 15, 18, 21 and 24, adjusted for center size. Negative values reflect a better mean VA in the ranibizumab group. Non-inferiority limit = -3.5 letters
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.26
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.75
         upper limit
    1.01
    Statistical analysis title
    BCVA by treatment regimen
    Statistical analysis description
    Difference in BCVA at 2 years, by treatment regimen. Difference is estimated using data from visits 0, 3, 6, 9, 12, 15, 18, 21 and 24, adjusted for center size. Negative values reflect a better mean VA in the continuous group. Non-inferiority limit = -3.5 letters
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.18
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.01
         upper limit
    0.75
    Statistical analysis title
    BCVA by drug: Baseline BCVA in fellow eye ≥75
    Comparison groups
    Ranibizumab: Baseline BCVA in fellow eye ≥75 v Bevacizumab: Baseline BCVA in fellow eye ≥75
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.3 [1]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.11
         upper limit
    1.57
    Notes
    [1] - p-value for interaction between baseline BCVA in fellow eye and drug = 0.78
    Statistical analysis title
    BCVA by drug: Baseline BCVA in fellow eye <75
    Comparison groups
    Ranibizumab: Baseline BCVA in fellow eye <75 v Bevacizumab: Baseline BCVA in fellow eye <75
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.8 [2]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.91
         upper limit
    3.01
    Notes
    [2] - p-value for interaction between baseline BCVA in fellow eye and drug = 0.78
    Statistical analysis title
    BCVA by regimen: Baseline BCVA in fellow eye ≥75
    Comparison groups
    Continuous: Baseline BCVA in fellow eye ≥75 v Discontinuous: Baseline BCVA in fellow eye ≥75
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.47 [3]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.59
         upper limit
    2.11
    Notes
    [3] - p-value for interaction between baseline BCVA in fellow eye and treatment regimen = 0.93
    Statistical analysis title
    BCVA by regimen: Baseline BCVA in fellow eye <75
    Comparison groups
    Continuous: Baseline BCVA in fellow eye <75 v Discontinuous: Baseline BCVA in fellow eye <75
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.29 [4]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.35
         upper limit
    1.59
    Notes
    [4] - p-value for interaction between baseline BCVA in fellow eye and treatment regimen = 0.93
    Statistical analysis title
    BCVA by drug: Baseline BCVA <55
    Comparison groups
    Ranibizumab: Baseline BCVA <55 v Bevacizumab: Baseline BCVA <55
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.022 [5]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -5.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.64
         upper limit
    -0.75
    Notes
    [5] - p-value for interaction between baseline BCVA and drug = 0.47
    Statistical analysis title
    BCVA by drug: Baseline BCVA ≥55
    Comparison groups
    Ranibizumab: Baseline BCVA ≥55 v Bevacizumab: Baseline BCVA ≥55
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.8 [6]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.44
         upper limit
    3.16
    Notes
    [6] - p-value for interaction between baseline BCVA and drug = 0.47
    Statistical analysis title
    BCVA by regimen: Baseline BCVA <55
    Comparison groups
    Continuous: Baseline BCVA <55 v Disontinuous: Baseline BCVA <55
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.15 [7]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.74
         upper limit
    1.19
    Notes
    [7] - p-value for interaction between baseline BCVA and treatment regimen = 0.89
    Statistical analysis title
    BCVA by regimen: Baseline BCVA ≥55
    Comparison groups
    Continuous: Baseline BCVA ≥55 v Disontinuous: Baseline BCVA ≥55
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.53 [8]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    1.9
    Notes
    [8] - p-value for interaction between baseline BCVA and treatment regimen = 0.89
    Statistical analysis title
    BCVA by drug: Baseline CNV size <6mm
    Comparison groups
    Bevacizumab: Baseline CNV size <6mm v Ranibizumab: Baseline CNV size <6mm
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.13 [9]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.15
         upper limit
    0.66
    Notes
    [9] - p-value for interaction between baseline CNV size and drug = 0.33
    Statistical analysis title
    BCVA by drug: Baseline CNV size ≥6mm
    Comparison groups
    Ranibizumab: Baseline CNV size ≥6mm v Bevacizumab: Baseline CNV size ≥6mm
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.69 [10]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.18
         upper limit
    4.81
    Notes
    [10] - p-value for interaction between baseline CNV size and drug = 0.33
    Statistical analysis title
    BCVA by regimen: Baseline CNV size <6mm
    Comparison groups
    Continuous arm: Baseline CNV size <6mm v Discontinuous arm: Baseline CNV size <6mm
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.02 [11]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.36
         upper limit
    -0.55
    Notes
    [11] - p-value for interaction between baseline CNV size and treatment regimen = 0.26
    Statistical analysis title
    BCVA by regimen: Baseline CNV size ≥6mm
    Comparison groups
    Continuous arm: Baseline CNV size ≥6mm v Discontinuous arm: Baseline CNV size ≥6mm
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.4 [12]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.28
         upper limit
    5.72
    Notes
    [12] - p-value for interaction between baseline CNV size and treatment regimen = 0.26
    Statistical analysis title
    BCVA by drug: Baseline lesion <50% CNV
    Comparison groups
    Ranibizumab: Baseline lesion <50% CNV v Bevacizumab: Baseline lesion <50% CNV
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.68 [13]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.26
         upper limit
    6.56
    Notes
    [13] - p-value for interaction between baseline lesion CNV proportion and drug = 0.36
    Statistical analysis title
    BCVA by drug: Baseline lesion ≥50% CNV
    Comparison groups
    Bevacizumab: Baseline lesion ≥50% CNV v Ranibizumab: Baseline lesion ≥50% CNV
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.18 [14]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.67
         upper limit
    0.89
    Notes
    [14] - p-value for interaction between baseline lesion CNV proportion and drug = 0.36
    Statistical analysis title
    BCVA by regimen: Baseline lesion <50% CNV
    Comparison groups
    Continuous: Baseline lesion <50% CNV v Discontinuous: Baseline lesion <50% CNV
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.13 [15]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.58
         upper limit
    1.21
    Notes
    [15] - p-value for interaction between baseline lesion CNV proportion and treatment regimen = 0.63
    Statistical analysis title
    BCVA by regimen: Baseline lesion ≥50% CNV
    Comparison groups
    Continuous: Baseline lesion ≥50% CNV v Discontinuous: Baseline lesion ≥50% CNV
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.49 [16]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.76
         upper limit
    1.81
    Notes
    [16] - p-value for interaction between baseline lesion CNV proportion and treatment regimen = 0.63
    Statistical analysis title
    BCVA by drug: Baseline RAP absent
    Comparison groups
    Ranibizumab: Baseline RAP absent v Bevacizumab: Baseline RAP absent
    Number of subjects included in analysis
    486
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.16 [17]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.55
         upper limit
    0.73
    Notes
    [17] - p-value for interaction between baseline RAP present/absent and drug = 0.71
    Statistical analysis title
    BCVA by drug: Baseline RAP present
    Comparison groups
    Ranibizumab: Baseline RAP present v Bevacizumab: Baseline RAP present
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.3 [18]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    3.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.27
         upper limit
    10.48
    Notes
    [18] - p-value for interaction between baseline RAP present/absent and drug = 0.71
    Statistical analysis title
    BCVA by regimen: Baseline RAP absent
    Comparison groups
    Continuous: Baseline RAP absent v Discontinuous: Baseline RAP absent
    Number of subjects included in analysis
    486
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.2 [19]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.38
         upper limit
    0.9
    Notes
    [19] - p-value for interaction between baseline RAP present/absent and treatment regimen = 0.85
    Statistical analysis title
    BCVA by regimen: Baseline RAP present
    Comparison groups
    Continuous: Baseline RAP present v Discontinuous: Baseline RAP present
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.41 [20]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.67
         upper limit
    3.95
    Notes
    [20] - p-value for interaction between baseline RAP present/absent and treatment regimen = 0.85
    Statistical analysis title
    BCVA by drug: Sensitivity analysis 1
    Statistical analysis description
    Sensitivity analysis of the primary outcome: excluding measurements taken 1 month later, when the main study visit was missed.
    Comparison groups
    Bevacizumab v Ranibizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.26
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.73
         upper limit
    1.03
    Statistical analysis title
    BCVA by treatment regimen: Sensitivity analysis 1
    Statistical analysis description
    Sensitivity analysis of the primary outcome: excluding measurements taken 1 month later, when the main study visit was missed.
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.19
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.98
         upper limit
    0.78
    Statistical analysis title
    BCVA by drug: Sensitivity analysis 2
    Statistical analysis description
    Sensitivity analysis of the primary outcome: including data only for the study visits at which all functional outcomes were assessed (visits 0, 3, 6, 12, 18 and 24).
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.16
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.08
         upper limit
    0.68
    Statistical analysis title
    BCVA by treatment regimen: Sensitivity analysis 2
    Statistical analysis description
    Sensitivity analysis of the primary outcome: including data only for the study visits at which all functional outcomes were assessed (visits 0, 3, 6, 12, 18 and 24).
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.19
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.97
         upper limit
    0.79

    Secondary: Frequencies of adverse events: Death from any cause

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    End point title
    Frequencies of adverse events: Death from any cause
    End point description
    Death from any cause
    End point type
    Secondary
    End point timeframe
    Duration of trial follow-up (maximum 2 years)
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Patients
        Yes
    15
    15
    10
    20
        No
    299
    281
    298
    182
    Statistical analysis title
    Death from any cause, by drug
    Statistical analysis description
    ORs < 1 reflect fewer deaths during the 2 years of follow-up in the ranibizumab arm.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.91
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    2.02
    Statistical analysis title
    Death from any cause, by treatment regimen
    Statistical analysis description
    ORs < 1 reflect fewer deaths during the 2 years of follow-up in the continuous arm.
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.05
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.22
         upper limit
    1.03

    Secondary: Frequencies of adverse events: Arteriothrombotic event or heart failure

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    End point title
    Frequencies of adverse events: Arteriothrombotic event or heart failure
    End point description
    Arteriothrombotic event (MI, stroke, death from a vascular cause) or heart failure
    End point type
    Secondary
    End point timeframe
    Duration of trial follow-up (maximum 2 years)
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Patients
        Yes
    20
    12
    12
    20
        No
    294
    284
    296
    282
    Statistical analysis title
    Arteriothrombotic or heart failure, by drug
    Statistical analysis description
    ORs < 1 reflect fewer events during the 2 years of follow-up in the ranibizumab arm.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.16
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    3.57
    Statistical analysis title
    Arteriothrombotic or heart failure, by regimen
    Statistical analysis description
    ORs < 1 reflect fewer events during the 2 years of follow-up in the continuous arm.
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.13
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    1.19

    Secondary: Frequencies of adverse events: Any vascular event

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    End point title
    Frequencies of adverse events: Any vascular event
    End point description
    Vascular events include arteriothrombotic events, heart failure, deep-vein thrombosis, pulmonary embolism, transient ischaemic attack, hospitalisation for angina, and non-ocular haemorrhage
    End point type
    Secondary
    End point timeframe
    Duration of trial follow-up (maximum 2 years)
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Patients
        Yes
    31
    19
    21
    29
        No
    283
    277
    287
    273
    Statistical analysis title
    Any vascular event, by drug
    Statistical analysis description
    ORs < 1 reflect fewer events during the 2 years of follow-up in the ranibizumab arm.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.1
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    3.01
    Statistical analysis title
    Any vascular event, by treatment regimen
    Statistical analysis description
    ORs < 1 reflect fewer events during the 2 years of follow-up in the continuous arm.
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.21
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    1.24

    Secondary: Frequencies of adverse events: Any vascular event or death

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    End point title
    Frequencies of adverse events: Any vascular event or death
    End point description
    End point type
    Secondary
    End point timeframe
    Duration of trial follow-up (maximum 2 years)
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Patients
        Yes
    38
    28
    27
    39
        No
    276
    268
    281
    263
    Statistical analysis title
    Any vascular event or death, by drug
    Statistical analysis description
    ORs < 1 reflect fewer events during the 2 years of follow-up in the ranibizumab arm.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.25
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    2.29
    Statistical analysis title
    Any vascular event or death, by treatment regimen
    Statistical analysis description
    ORs < 1 reflect fewer events during the 2 years of follow-up in the continuous arm.
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.1
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    1.09

    Secondary: Frequencies of adverse events: Any systemic event

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    End point title
    Frequencies of adverse events: Any systemic event
    End point description
    ≥1 serious systemic event (includes any non-ocular serious adverse event)
    End point type
    Secondary
    End point timeframe
    Duration of trial follow-up (maximum 2 years)
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Patients
        Yes
    81
    80
    74
    87
        No
    233
    216
    234
    215
    Statistical analysis title
    Any systemic event, by drug
    Statistical analysis description
    ORs < 1 reflect fewer events during the 2 years of follow-up in the ranibizumab arm
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.82
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1.39
    Statistical analysis title
    Any systemic event, by treatment regimen
    Statistical analysis description
    ORs < 1 reflect fewer events during the 2 years of follow-up in the continuous arm
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.16
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.11

    Secondary: Health-related quality of life: EQ-5D

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    End point title
    Health-related quality of life: EQ-5D
    End point description
    For the EQ-5D utility index, higher summary scores represent better utility.
    End point type
    Secondary
    End point timeframe
    Participants completed the EQ-5D at visits 0, 3, 12 and 24
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Score
        median (inter-quartile range (Q1-Q3))
    0.85 (0.73 to 1.00)
    0.85 (0.73 to 1.00)
    0.85 (0.73 to 1.00)
    0.85 (0.73 to 1.00)
    Statistical analysis title
    EQ-5D score, by drug
    Statistical analysis description
    For EQ-5D no suitable transformation could be found and so data were dichotomized as ‘perfect health’ (EQ-5D score of 1) compared with less than perfect health. ORs <1 reflect higher quality of life during the 2 years of follow-up in the ranibizumab arm.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.51
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.25
    Statistical analysis title
    EQ-5D score, by treatment regimen
    Statistical analysis description
    For EQ-5D no suitable transformation could be found and so data were dichotomized as ‘perfect health’ (EQ-5D score of 1) compared with less than perfect health. ORs <1 reflect higher quality of life during the 2 years of follow-up in the continuous arm
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.64
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1.29

    Secondary: Health-related quality of life: MacDQol

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    End point title
    Health-related quality of life: MacDQol
    End point description
    MacDQol (Macular disease Dependent Quality of Life) is an instrument designed to assess macular disease-specific quality of life. Lower scores represent less impact of nAMD on quality of life.
    End point type
    Secondary
    End point timeframe
    Administered by telephone after visits 3, 12 and 24.
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Score
        median (inter-quartile range (Q1-Q3))
    -1.5 (-2.8 to -0.3)
    -1.4 (-2.7 to -0.4)
    -1.3 (-2.7 to -0.3)
    -1.6 (-3.0 to -0.4)
    Statistical analysis title
    MacDQol, by drug
    Statistical analysis description
    For MacDQoL, the outcome was transformed from original scale of –9 to +3 to a scale of –3 to +9, and analysed using a log transformation. The GMR is, therefore, interpreted as the GMR of the MacDQoL score, and not of the MacDQoL score directly. GMR <1 reflect higher quality of life during the 2 years of follow-up in the ranibizumab arm
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.74
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.78
         upper limit
    1.42
    Statistical analysis title
    MacDQol, by treatment regimen
    Statistical analysis description
    For MacDQoL, the outcome was transformed from original scale of –9 to +3 to a scale of –3 to +9, and analysed using a log transformation. The GMR is, therefore, interpreted as the GMR of the MacDQoL score, and not of the MacDQoL score directly. GMR <1 reflect higher quality of life during the 2 years of follow-up in the continuous arm
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.73
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.28

    Secondary: Treatment satisfaction: MacTSQ

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    End point title
    Treatment satisfaction: MacTSQ
    End point description
    MacTSQ (Macular disease Treatment Satisfaction Questionnaire) is an instrument designed to assess patients’ satisfaction with treatment for nAMD. Higher summary scores represent a higher treatment satisfaction.
    End point type
    Secondary
    End point timeframe
    Administered by telephone after visits 3, 12 and 24.
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Score
        median (inter-quartile range (Q1-Q3))
    66 (61.5 to 70)
    65 (60 to 69)
    65.5 (61 to 69)
    66 (60 to 69)
    Statistical analysis title
    MacTSQ, by drug
    Statistical analysis description
    For MacTSQ at 2 years, no suitable transformation could be found and so data were dichotomized (MacTSQ < median TSQ score over all time points vs. ≥ median TSQ score over all time points). ORs <1 reflect higher quality of life during the 2 years of follow-up in the ranibizumab arm.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.23
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.16
    Statistical analysis title
    MacTSQ, by treatment regimen
    Statistical analysis description
    For MacTSQ at 2 years, no suitable transformation could be found and so data were dichotomized (MacTSQ < median TSQ score over all time points vs. ≥ median TSQ score over all time points). ORs <1 reflect higher quality of life during the 2 years of follow-up in the continuous arm.
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.47
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.68

    Secondary: Resource use: Injection consultation

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    End point title
    Resource use: Injection consultation
    End point description
    Measured as the number of episodes of injection consultations.
    End point type
    Secondary
    End point timeframe
    Resource use used by the average patient during 2-year study period
    End point values
    Discontinuous bevacizumab Continuous bevacizumab Discontinuous ranibizumab Continuous ranibizumab
    Number of subjects analysed
    146
    150
    156
    158
    Units: Number of consultations
        arithmetic mean (confidence interval 95%)
    13.0 (12.3 to 13.8)
    22.0 (21.6 to 22.4)
    12.7 (12.0 to 13.4)
    21.7 (21.2 to 22.1)
    Statistical analysis title
    Injection consultations, by drug
    Statistical analysis description
    Ranibizumab vs. bevacizumab
    Comparison groups
    Discontinuous bevacizumab v Continuous bevacizumab v Discontinuous ranibizumab v Continuous ranibizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.4
    Statistical analysis title
    Injection consultations, by treatment regimen
    Statistical analysis description
    Continuous vs. discontinuous
    Comparison groups
    Discontinuous bevacizumab v Continuous bevacizumab v Discontinuous ranibizumab v Continuous ranibizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.3
         upper limit
    9.7

    Secondary: Resource use: Monitoring consultations

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    End point title
    Resource use: Monitoring consultations
    End point description
    Measured as the number of episodes of monitoring consultations.
    End point type
    Secondary
    End point timeframe
    Resource use used by the average patient during 2-year study period
    End point values
    Discontinuous bevacizumab Continuous bevacizumab Discontinuous ranibizumab Continuous ranibizumab
    Number of subjects analysed
    146
    150
    156
    158
    Units: Number of consultations
        arithmetic mean (confidence interval 95%)
    13.2 (12.7 to 13.8)
    7.1 (6.9 to 7.4)
    13.7 (13.1 to 14.2)
    7.6 (7.4 to 7.9)
    Statistical analysis title
    Monitoring consultations, by drug
    Statistical analysis description
    Ranibizumab vs. bevacizumab
    Comparison groups
    Continuous bevacizumab v Discontinuous ranibizumab v Discontinuous bevacizumab v Continuous ranibizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.9
    Statistical analysis title
    Monitoring consultations, by treatment regimen
    Statistical analysis description
    Continuous vs. discontinuous
    Comparison groups
    Discontinuous bevacizumab v Continuous bevacizumab v Discontinuous ranibizumab v Continuous ranibizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -6.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.5
         upper limit
    -5.6

    Secondary: Resource use: Bed-days linked to expected SAEs

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    End point title
    Resource use: Bed-days linked to expected SAEs
    End point description
    Measured as the number of episodes of bed-days linked to expected SAEs.
    End point type
    Secondary
    End point timeframe
    Resource use used by the average patient during 2-year study period
    End point values
    Discontinuous bevacizumab Continuous bevacizumab Discontinuous ranibizumab Continuous ranibizumab
    Number of subjects analysed
    146
    150
    156
    158
    Units: Days
        arithmetic mean (confidence interval 95%)
    1.0 (-0.2 to 2.1)
    0.8 (0.1 to 1.4)
    0.7 (0.2 to 1.2)
    0.3 (0.0 to 0.6)
    Statistical analysis title
    Bed-days, by drug (continuous arm)
    Statistical analysis description
    Continuous arm: Ranibizumab vs. bevacizumab
    Comparison groups
    Continuous bevacizumab v Continuous ranibizumab
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.3
    Statistical analysis title
    Bed-days, by drug (discontinuous arm)
    Statistical analysis description
    Discontinuous arm: Ranibizumab vs. bevacizumab
    Comparison groups
    Discontinuous bevacizumab v Discontinuous ranibizumab
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    1
    Statistical analysis title
    Bed-days, by treatment regimen (ranibizumab arm)
    Statistical analysis description
    Ranibizumab arm: Continuous vs. discontinuous
    Comparison groups
    Discontinuous ranibizumab v Continuous ranibizumab
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.3
    Statistical analysis title
    Bed-days, by treatment regimen (bevacizumab)
    Statistical analysis description
    Bevacizumab arm: Continuous vs. discontinuous
    Comparison groups
    Discontinuous bevacizumab v Continuous bevacizumab
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    1.1

    Secondary: Resource use: Ambulatory consultations

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    End point title
    Resource use: Ambulatory consultations
    End point description
    Measured as the number of episodes of ambulatory resource use, when an ‘episode’ encompasses all contacts with medical professionals on the same date. For example, seeing a GP and a practice nurse on the same date is counted as one ambulatory consultation in this analysis.
    End point type
    Secondary
    End point timeframe
    Resource use used by the average patient during 2-year study period. Consultations within 30 days of expected (S)AEs.
    End point values
    Discontinuous bevacizumab Continuous bevacizumab Discontinuous ranibizumab Continuous ranibizumab
    Number of subjects analysed
    146
    150
    156
    158
    Units: Number of consultations
        arithmetic mean (confidence interval 95%)
    2.8 (2.2 to 3.5)
    3.1 (2.4 to 3.7)
    2.8 (2.3 to 3.3)
    3.1 (2.4 to 3.9)
    Statistical analysis title
    Ambulatory consultations, by drug (continuous)
    Statistical analysis description
    Continuous arm: Ranibizumab vs. bevacizumab
    Comparison groups
    Continuous bevacizumab v Continuous ranibizumab
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    1.1
    Statistical analysis title
    Ambulatory consultations, by drug (discontinuous)
    Statistical analysis description
    Discontinuous arm: Ranibizumab vs. bevacizumab
    Comparison groups
    Discontinuous bevacizumab v Discontinuous ranibizumab
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    0.8
    Statistical analysis title
    Ambulatory consultations, by regimen (ranibizumab)
    Statistical analysis description
    Ranibizumab arm: Continuous vs. discontinuous
    Comparison groups
    Discontinuous ranibizumab v Continuous ranibizumab
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    1.2
    Statistical analysis title
    Ambulatory consultations, by regimen (bevacizumab)
    Statistical analysis description
    Bevacizumab arm: Continuous vs. discontinuous
    Comparison groups
    Discontinuous bevacizumab v Continuous bevacizumab
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    1.1

    Secondary: Resource use: Changes in medications

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    End point title
    Resource use: Changes in medications
    End point description
    Changes in medications associated with expected (S)AEs.
    End point type
    Secondary
    End point timeframe
    Resource use used by the average patient during 2-year study period.
    End point values
    Discontinuous bevacizumab Continuous bevacizumab Discontinuous ranibizumab Continuous ranibizumab
    Number of subjects analysed
    146
    150
    156
    158
    Units: Number of changes
        arithmetic mean (confidence interval 95%)
    3.0 (2.5 to 3.6)
    2.6 (2.2 to 3.1)
    2.8 (2.2 to 3.4)
    3.0 (2.4 to 3.6)
    Statistical analysis title
    Changes in medication, by drug (continuous)
    Statistical analysis description
    Continuous arm: Ranibizumab vs. bevacizumab
    Comparison groups
    Continuous bevacizumab v Continuous ranibizumab
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    1.1
    Statistical analysis title
    Changes in medication, by drug (discontinuous)
    Statistical analysis description
    Discontinuous arm: Ranibizumab vs. bevacizumab
    Comparison groups
    Discontinuous bevacizumab v Discontinuous ranibizumab
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.6
    Statistical analysis title
    Changes in medication, by regimen (ranibizumab)
    Statistical analysis description
    Ranibizumab arm: Continuous vs. discontinuous
    Comparison groups
    Discontinuous ranibizumab v Continuous ranibizumab
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    1
    Statistical analysis title
    Changes in medication, by regimen (bevacizumab)
    Statistical analysis description
    Bevacizumab arm: Continuous vs. discontinuous
    Comparison groups
    Continuous bevacizumab v Discontinuous bevacizumab
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    0.3

    Secondary: Cost effectiveness: QALYs

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    End point title
    Cost effectiveness: QALYs
    End point description
    End point type
    Secondary
    End point timeframe
    Mean QUALYs per patient over the 2-year trial period.
    End point values
    Discontinuous bevacizumab Continuous bevacizumab Discontinuous ranibizumab Continuous ranibizumab
    Number of subjects analysed
    146
    150
    156
    158
    Units: QUALY
        arithmetic mean (confidence interval 95%)
    1.584 (1.583 to 1.630)
    1.604 (1.563 to 1.645)
    1.582 (1.530 to 1.634)
    1.608 (1.565 to 1.651)
    Statistical analysis title
    QALY, by drug (continuous)
    Statistical analysis description
    Continuous arm: Ranibizumab vs. bevacizumab
    Comparison groups
    Continuous bevacizumab v Continuous ranibizumab
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.046
         upper limit
    0.054
    Statistical analysis title
    QALY, by drug (discontinuous)
    Statistical analysis description
    Discontinuous arm: Ranibizumab vs. bevacizumab
    Comparison groups
    Discontinuous bevacizumab v Discontinuous ranibizumab
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.064
         upper limit
    0.06
    Statistical analysis title
    QALY, by treatment regimen (ranibizumab)
    Statistical analysis description
    Ranibizumab arm: Continuous vs. discontinuous
    Comparison groups
    Discontinuous ranibizumab v Continuous ranibizumab
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.032
         upper limit
    0.085
    Statistical analysis title
    QALY, by treatment regimen (bevacizumab)
    Statistical analysis description
    Bevacizumab arm: Continuous vs. discontinuous
    Comparison groups
    Discontinuous bevacizumab v Continuous bevacizumab
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.032
         upper limit
    0.071

    Secondary: Clinical measures of vision: Near visual acuity

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    End point title
    Clinical measures of vision: Near visual acuity
    End point description
    Near visual acuity (NVA) is measured in logMAR units using charts that utilise words of specific character sizes and lengths.
    End point type
    Secondary
    End point timeframe
    Measured at 0, 3, 6, 12, 18 and 24 months
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: logMAR
        arithmetic mean (standard deviation)
    0.55 ± 0.39
    0.61 ± 0.42
    0.58 ± 0.40
    0.58 ± 0.41
    Statistical analysis title
    Near visual acuity, by drug
    Statistical analysis description
    Difference in NVA at 2 years, by drug allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. GMR values of < 1 reflect a better outcome in the ranibizumab group.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.23
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.04
    Statistical analysis title
    Near visual acuity, by treatment regimen
    Statistical analysis description
    Difference in NVA at 2 years, by treatment regimen allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. GMR values of < 1 reflect a better outcome in the continuous group.
    Comparison groups
    Discontinuous v Continuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.04
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    0.99

    Secondary: Clinical measures of vision: Reading index

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    End point title
    Clinical measures of vision: Reading index
    End point description
    Reading index is a derivative of reading speed. Reading speed is a psychophysical test, which measures ability to read a string of words without reference to context. It tests the ability of the eye to scan along a line of words, and this function is impaired if visual deficits are present in the parafoveal retina. Reading speed is measured using a print size subtending a visual angle that is 0.1 logMAR larger than the threshold NVA and expressed in units of words read per minute. The reading index is the reading speed divided by the size of print read and thus makes allowance for the visual angle.
    End point type
    Secondary
    End point timeframe
    Measured at 0, 3, 6, 12, 18 and 24 months
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Words read
        median (inter-quartile range (Q1-Q3))
    50.9 (22.8 to 93.7)
    52.5 (9.7 to 90.6)
    46.3 (11.4 to 84.0)
    55.4 (19.0 to 97.6)
    Statistical analysis title
    Reading index, by drug
    Statistical analysis description
    Difference in reading index at 2 years, by drug allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. Negative values reflect a better outcome in the ranibizumab group.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.7
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.29
         upper limit
    5.61
    Statistical analysis title
    Reading index, by treatment regimen
    Statistical analysis description
    Difference in reading index at 2 years, by treatment regimen allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. Negative values reflect a better outcome in the continuous group.
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.93
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.27
         upper limit
    6.62

    Secondary: Clinical measures of vision: Contrast sensitivity

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    End point title
    Clinical measures of vision: Contrast sensitivity
    End point description
    Contrast sensitivity is a global measure of macular function. It has been suggested that it represents a better surrogate marker for visual function than BCVA by virtue of the fact that some studies have observed better correlation with patient-reported outcomes.
    End point type
    Secondary
    End point timeframe
    Measured at 0, 3, 6, 12, 18 and 24 months
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Letters
        arithmetic mean (standard deviation)
    28.1 ± 6.0
    28.3 ± 5.8
    28.7 ± 5.4
    27.7 ± 6.3
    Statistical analysis title
    Contrast sensitivity, by drug
    Statistical analysis description
    Difference in contrast sensitivity at 2 years, by drug allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. Negative values reflect a better outcome in the ranibizumab group.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.62
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.62
         upper limit
    1.04
    Statistical analysis title
    Contrast sensitivity, by treatment regimen
    Statistical analysis description
    Difference in contrast sensitivity at 2 years, by treatment regimen allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. Negative values reflect a better outcome in the continuous group.
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.011
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    -0.25

    Secondary: Lesion morphology: Geographic atrophy

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    End point title
    Lesion morphology: Geographic atrophy
    End point description
    New GA during follow-up in trial. Assessed from colour and FFA. Area ≥ 175 μm greatest linear dimension with two or more relevant features in colour images (well-defined margins; visibility of choroidal vessels; scalloped edges) and consistent finding on FFA (early hyperfluorescence, persisting through the FFA sequence and fading in late images)
    End point type
    Secondary
    End point timeframe
    During follow-up in trial. Measured at baseline, 12 and 24 months.
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Patients
    86
    91
    101
    76
    Statistical analysis title
    Geographic atrophy, by drug
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the ranibizumab group
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.46
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.25
    Statistical analysis title
    Geographic atrophy, by treatment regimen
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the continuous group
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.033
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    2.11

    Secondary: Lesion morphology: Dye leakage

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    End point title
    Lesion morphology: Dye leakage
    End point description
    Dye leakage on angiogram (assesed from FFA). Areas of featureless hyperfluorescence that increase in the late frames and which may also exhibit well delineated hyperfluorescence in the early frames.
    End point type
    Secondary
    End point timeframe
    Measured at baseline, 12 and 24 months.
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Patients
    101
    89
    86
    104
    Statistical analysis title
    Dye leakage, by drug
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the ranibizumab group
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.46
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.67
    Statistical analysis title
    Dye leakage, by treatment regimen
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the continuous group
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.11
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.07

    Secondary: Lesion morphology: Fluid

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    End point title
    Lesion morphology: Fluid
    End point description
    Any fluid on OCT
    End point type
    Secondary
    End point timeframe
    Measured at 0, 3, 6, 9, 12, 15, 18, 21 and 24 months
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Patients
    127
    141
    112
    156
    Statistical analysis title
    Fluid, by drug
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the ranibizumab group
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.065
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    1.02
    Statistical analysis title
    Fluid, by treatment regimen
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the continuous group
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    0.67

    Secondary: Lesion morphology: Lesion present

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    End point title
    Lesion morphology: Lesion present
    End point description
    Assessed from FFA
    End point type
    Secondary
    End point timeframe
    Measured at baseline, 12 and 24 months.
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Patients
    142
    127
    123
    146
    Statistical analysis title
    Lesion present, by drug
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the ranibizumab group
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.44
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.67
    Statistical analysis title
    Lesion present, by treatment regimen
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the continuous group
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.024
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    0.95

    Secondary: Lesion morphology: Retinal plus subretinal fluid thickness at fovea

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    End point title
    Lesion morphology: Retinal plus subretinal fluid thickness at fovea
    End point description
    Assessed from OCT. Foveal neuroretinal thickness (a linear measurement of the distance between the inner and outer boundary of the neurosensory retina at the foveal centre) plus SRF thickness at fovea (height of hyporeflective region separating the RPE band from the outer boundary of the neurosensory retina at the foveal centre).
    End point type
    Secondary
    End point timeframe
    Measured at 0, 3, 6, 9, 12, 15, 18, 21 and 24 months.
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: µm
        arithmetic mean (standard deviation)
    163.5 ± 77.7
    172.7 ± 95.7
    161.7 ± 84.2
    174.4 ± 89.4
    Statistical analysis title
    Retinal plus SRF thickness, by drug
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the ranibizumab group
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.75
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.08
    Statistical analysis title
    Retinal plus SRF thickness, by treament regimen
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the continuous group
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.046
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1

    Secondary: Lesion morphology: Total lesion thickness at the fovea

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    End point title
    Lesion morphology: Total lesion thickness at the fovea
    End point description
    Assessed from OCT. Sum of foveal neuroretinal thickness (a linear measurement of the distance between the inner and outer boundary of the neurosensory retina at the foveal centre), SRF thickness at fovea (height of hyporeflective region separating the RPE band from the outer boundary of the neurosensory retina at the foveal centre) and PED (Elevation of the hyper-reflective band corresponding to the RPE and or scar at the foveal centre).
    End point type
    Secondary
    End point timeframe
    Measured at 0, 3, 6, 9, 12, 15, 18, 21 and 24 months.
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: µM
        arithmetic mean (standard deviation)
    322.4 ± 137.3
    331 ± 144.2
    314.7 ± 137.1
    338.5 ± 143.3
    Statistical analysis title
    Total lesion thickness, by drug
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the ranibizumab group
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.24
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.03
    Statistical analysis title
    Total lesion thickness, by treatment regimen
    Statistical analysis description
    Ratios of < 1 reflect better outcomes in the continuous group
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0035
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    0.97

    Secondary: Best corrected visual acuity at 1 year

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    End point title
    Best corrected visual acuity at 1 year
    End point description
    Results of interim analysis: BCVA after all patients have been followed for 1 year after starting treatment.
    End point type
    Secondary
    End point timeframe
    Measured at 0, 3, 6, and 12 months
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308
    302
    Units: Letters
        arithmetic mean (standard deviation)
    69.0 ± 16.0
    66.1 ± 17.4
    66.8 ± 17.4
    68.4 ± 16.1
    Statistical analysis title
    BCVA at 1 year, by drug
    Statistical analysis description
    Difference in BCVA at 1 year, by drug allocation. Difference is estimated using data from visits 0, 3, 6 and 12, adjusted for center size. Negative values reflect a better mean VA in the ranibizumab group. Non-inferiority limit = -3.5 letters
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.056
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.04
         upper limit
    0.06
    Statistical analysis title
    BCVA at 1 year, by treatment regimen
    Statistical analysis description
    Difference in BCVA at 1 year, by treatment regimen allocation. Difference is estimated using data from visits 0, 3, 6 and 12, adjusted for center size. Negative values reflect a better mean VA in the continuous group. Non-inferiority limit = -3.5 letters
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.74
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    1.7

    Secondary: Survival free from treatment failure

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    End point title
    Survival free from treatment failure
    End point description
    Treatment failure: Satisfying one or more of the criteria for re-treatment.
    End point type
    Secondary
    End point timeframe
    Re-treatment criteria collected monthly from month 3-24.
    End point values
    Ranibizumab Bevacizumab Continuous Discontinuous
    Number of subjects analysed
    314
    296
    308 [21]
    302
    Units: Months
        median (inter-quartile range (Q1-Q3))
    5.1 (3.7 to 16.8)
    4.9 (3.2 to 14.0)
    7.6 (3.2 to 24.0)
    4.4 (3.2 to 6.9)
    Notes
    [21] - 75th percentile (Q3) not reached. Maximum duration (24 months) entered.
    Statistical analysis title
    Time to treatment failure, by drug
    Statistical analysis description
    Hazard ratio (bevacizumab–ranibizumab)
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.18
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.94
         upper limit
    1.36
    Statistical analysis title
    Time to treatment failure, by regimen
    Statistical analysis description
    Hazard ratio (discontinuous–continuous)
    Comparison groups
    Continuous v Discontinuous
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.61
         upper limit
    2.35

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events, both serious and non-serious, were recorded at each visit.
    Adverse event reporting additional description
    All expected adverse events and unexpected adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA, McLean, VA, USA). All SAEs were reviewed by senior clinicians masked to treatment allocation.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Ranibizumab
    Reporting group description
    Intravitreal injections of ranibizumab (0.5mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

    Reporting group title
    Bevacizumab
    Reporting group description
    Intravitreal injections of bevacizumab (1.25mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

    Reporting group title
    Continuous
    Reporting group description
    Monthly treatment.

    Reporting group title
    Discontinuous
    Reporting group description
    Treated if pre specified clinical and OCT criteria for active disease were met. If re-treatment was needed, a further cycle of three doses was given monthly.

    Serious adverse events
    Ranibizumab Bevacizumab Continuous Discontinuous
    Total subjects affected by serious adverse events
         subjects affected / exposed
    87 / 314 (27.71%)
    84 / 296 (28.38%)
    79 / 308 (25.65%)
    92 / 302 (30.46%)
         number of deaths (all causes)
    15
    15
    10
    20
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    Gallbladder cancer
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 314 (0.00%)
    2 / 296 (0.68%)
    1 / 308 (0.32%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic neoplasm malignant
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    5 / 314 (1.59%)
    2 / 296 (0.68%)
    3 / 308 (0.97%)
    4 / 302 (1.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    Mantle cell lymphoma
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Mesothelioma
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    2 / 314 (0.64%)
    1 / 296 (0.34%)
    3 / 308 (0.97%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 314 (0.00%)
    2 / 296 (0.68%)
    1 / 308 (0.32%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    3 / 314 (0.96%)
    1 / 296 (0.34%)
    2 / 308 (0.65%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Poor peripheral circulation
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Analgesic therapy
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm repair
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac pacemaker insertion
         subjects affected / exposed
    2 / 314 (0.64%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract operation
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chemotherapy
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    0 / 314 (0.00%)
    2 / 296 (0.68%)
    1 / 308 (0.32%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithotomy
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cochlea implant
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery bypass
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterostomy
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrostomy tube insertion
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 314 (0.32%)
    2 / 296 (0.68%)
    1 / 308 (0.32%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Knee operation
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung lobectomy
         subjects affected / exposed
    2 / 314 (0.64%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastectomy
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral nerve operation
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sebaceous cyst excision
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin neoplasm excision
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgery
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transurethral bladder resection
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transurethral prostatectomy
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vulval operation
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    15 / 314 (4.78%)
    15 / 296 (5.07%)
    10 / 308 (3.25%)
    20 / 302 (6.62%)
         occurrences causally related to treatment / all
    4 / 15
    3 / 15
    2 / 10
    5 / 20
         deaths causally related to treatment / all
    4 / 15
    3 / 15
    2 / 10
    5 / 20
    Multi-organ failure
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Swelling
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Convalescent
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 314 (0.64%)
    0 / 296 (0.00%)
    2 / 308 (0.65%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 314 (0.96%)
    3 / 296 (1.01%)
    3 / 308 (0.97%)
    3 / 302 (0.99%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    Investigations
    Biopsy
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biopsy vulva
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endoscopy upper gastrointestinal tract
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IOP increased
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    7 / 314 (2.23%)
    2 / 296 (0.68%)
    3 / 308 (0.97%)
    6 / 302 (1.99%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 314 (0.32%)
    3 / 296 (1.01%)
    2 / 308 (0.65%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 314 (0.64%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Upper limb fracture
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    7 / 314 (2.23%)
    3 / 296 (1.01%)
    6 / 308 (1.95%)
    4 / 302 (1.32%)
         occurrences causally related to treatment / all
    4 / 7
    2 / 3
    3 / 6
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 314 (0.32%)
    2 / 296 (0.68%)
    1 / 308 (0.32%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 314 (0.00%)
    3 / 296 (1.01%)
    0 / 308 (0.00%)
    3 / 302 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
    Cardiac failure
         subjects affected / exposed
    7 / 314 (2.23%)
    2 / 296 (0.68%)
    5 / 308 (1.62%)
    4 / 302 (1.32%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cor pulmonale
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Left ventricular failure
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MI
         subjects affected / exposed
    4 / 314 (1.27%)
    4 / 296 (1.35%)
    2 / 308 (0.65%)
    6 / 302 (1.99%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 5
    2 / 2
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 314 (0.00%)
    2 / 296 (0.68%)
    0 / 308 (0.00%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    7 / 314 (2.23%)
    3 / 296 (1.01%)
    4 / 308 (1.30%)
    6 / 302 (1.99%)
         occurrences causally related to treatment / all
    6 / 7
    2 / 3
    3 / 4
    5 / 6
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Facial paresis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frontotemporal dementia
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Unresponsive to stimuli
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden hearing loss
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blindness
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract traumatic
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RPE tear
         subjects affected / exposed
    3 / 314 (0.96%)
    1 / 296 (0.34%)
    2 / 308 (0.65%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-study eye: AMD
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-study eye: Cataract
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-study eye: Endophthalmitis
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-study eye: Herpes zoster
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-study eye: Wound evisceration
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 314 (0.64%)
    1 / 296 (0.34%)
    2 / 308 (0.65%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 314 (0.64%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    3 / 302 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 314 (1.27%)
    5 / 296 (1.69%)
    5 / 308 (1.62%)
    4 / 302 (1.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    3 / 314 (0.96%)
    5 / 296 (1.69%)
    3 / 308 (0.97%)
    5 / 302 (1.66%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
    1 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    1 / 308 (0.32%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 314 (0.32%)
    2 / 296 (0.68%)
    3 / 308 (0.97%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 296 (0.00%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Ranibizumab Bevacizumab Continuous Discontinuous
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    294 / 314 (93.63%)
    276 / 296 (93.24%)
    289 / 308 (93.83%)
    281 / 302 (93.05%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified
         subjects affected / exposed
    15 / 314 (4.78%)
    9 / 296 (3.04%)
    11 / 308 (3.57%)
    13 / 302 (4.30%)
         occurrences all number
    15
    10
    12
    13
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    55 / 314 (17.52%)
    51 / 296 (17.23%)
    58 / 308 (18.83%)
    48 / 302 (15.89%)
         occurrences all number
    72
    66
    79
    59
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    19 / 314 (6.05%)
    15 / 296 (5.07%)
    13 / 308 (4.22%)
    21 / 302 (6.95%)
         occurrences all number
    23
    16
    14
    25
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    40 / 314 (12.74%)
    49 / 296 (16.55%)
    46 / 308 (14.94%)
    43 / 302 (14.24%)
         occurrences all number
    52
    61
    56
    57
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    10 / 314 (3.18%)
    7 / 296 (2.36%)
    9 / 308 (2.92%)
    8 / 302 (2.65%)
         occurrences all number
    10
    8
    10
    8
    Social circumstances
    Social circumstances
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 296 (0.34%)
    0 / 308 (0.00%)
    1 / 302 (0.33%)
         occurrences all number
    0
    1
    0
    1
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    6 / 314 (1.91%)
    7 / 296 (2.36%)
    3 / 308 (0.97%)
    10 / 302 (3.31%)
         occurrences all number
    7
    7
    3
    11
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    125 / 314 (39.81%)
    122 / 296 (41.22%)
    119 / 308 (38.64%)
    128 / 302 (42.38%)
         occurrences all number
    218
    199