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    Clinical Trial Results:
    Five year observational follow-up of the IVAN trial cohort: a study of function and morphology

    Summary
    EudraCT number
    2015-002608-97
    Trial protocol
    GB  
    Global end of trial date
    01 Dec 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Mar 2019
    First version publication date
    24 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14206UC-AC
    Additional study identifiers
    ISRCTN number
    ISRCTN92166560
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Belfast Health & Social Care Trust
    Sponsor organisation address
    Research Office, 2nd Floor King Edward Building, Royal Hospitals, Grosvenor Road, Belfast, United Kingdom, BT12 6BA
    Public contact
    Usha Chakravarthy, Belfast Health and Social Care Trust, +44 02890632527, u.chakravarthy@qub.ac.uk
    Scientific contact
    Usha Chakravarthy, Belfast Health and Social Care Trust, +44 02890632527, alison.murphy@belfasttrust.hscni.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the care of IVAN participants in the NHS, and changes to their vision, since the end of the IVAN trial in order to better inform future NHS strategies for treatment of wet Age-related Macular Degeneration. To compare outcomes by original randomised allocations at 5-7 years after randomisation.
    Protection of trial subjects
    Participants were in an observational study of usual care during a period after IMP was discontinued and the trial was closed. This was a follow up study of long term outcomes and participants were not put at any risk.
    Background therapy
    Not applicable- see above
    Evidence for comparator
    Not applicable- see above
    Actual start date of recruitment
    26 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 532
    Worldwide total number of subjects
    532
    EEA total number of subjects
    532
    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)
    19
    From 65 to 84 years
    384
    85 years and over
    129

    Subject disposition

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    Recruitment
    Recruitment details
    All participants who did not die or withdraw from the IVAN trial were invited to participate in the follow up study by either attending a single research visit in person, for eye examinations and a questionnaire, or completing a questionnaire by post. They were also be offered the option to withdraw from the study.

    Pre-assignment
    Screening details
    Of the 610 patients recruited to the IVAN trial, 532 were included in the follow-up study; 66 died or withdrew during the IVAN trial, 7 were at a single site that did not participate in the extended IVAN follow up and 5 withdrew during the extended follow up. 124 of the 532 participants had died by the time of follow up.

    Period 1
    Period 1 title
    Follow-up cohort (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    The participants were initially randomised to one of four treatment regimens in the original IVAN trial, and participants, clinical and trial personnel were masked. At the start of this study, after exiting the trial, participants were treated in the NHS. Although health professionals and participants have not been masked to ongoing care, ophthalmologists managing participants are extremely unlikely to know the original experimental allocation

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Follow-up cohort
    Arm description
    All participants in the extended follow-up study Of the 532 participants in the extended follow-up study, 124 had died and 199 agreed to attend a specific research visit. Data were collected passively for non-attenders (124 deceased patients and 209 who did not wish to attend a research visit)
    Arm type
    Overall

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    IVAN randomised allocation: Ranibizumab
    Arm description
    This is an observational follow up of the original participants who were enrolled in the IVAN trial. The participants were initially randomised to one of four treatment regimens in the original IVAN trial and after exiting the trial, participants were treated in the NHS. The follow up study looked at the long term outcomes of these patients and is purely observational in that there was data collection but no intervention. This arm is the treatment allocation of the original IVAN trial.
    Arm type
    IVAN trial allocation (reference group)

    Investigational medicinal product name
    Lucentis
    Investigational medicinal product code
    Other name
    Ranibizumab
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Drug dose during IVAN trial: 0.5 mg

    Arm title
    IVAN randomised allocation: Bevacizumab
    Arm description
    This is an observational follow up of the original participants who were enrolled in the IVAN trial. The participants were initially randomised to one of four treatment regimens in the original IVAN trial and after exiting the trial, participants were treated in the NHS. The follow up study looked at the long term outcomes of these patients and is purely observational in that there was data collection but no intervention. This arm is the treatment allocation of the original IVAN trial.
    Arm type
    IVAN trial allocation

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Drug dose during IVAN trial: 1.25 mg

    Arm title
    IVAN randomised allocation: Continuous
    Arm description
    This is an observational follow up of the original participants who were enrolled in the IVAN trial. The participants were initially randomised to one of four treatment regimens in the original IVAN trial and after exiting the trial, participants were treated in the NHS. The follow up study looked at the long term outcomes of these patients and is purely observational in that there was data collection but no intervention. This arm is the treatment allocation of the original IVAN trial.
    Arm type
    IVAN trial allocation (reference group)

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    IVAN randomised allocation: Discontinuous
    Arm description
    This is an observational follow up of the original participants who were enrolled in the IVAN trial. The participants were initially randomised to one of four treatment regimens in the original IVAN trial and after exiting the trial, participants were treated in the NHS. The follow up study looked at the long term outcomes of these patients and is purely observational in that there was data collection but no intervention. This arm is the treatment allocation of the original IVAN trial.
    Arm type
    IVAN trial allocation

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Intralesional macular atrophy (ILMA) absent in study eye
    Arm description
    Intralesional macular atrophy (ILMA) absent in study eye at extended follow up. Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA)) during extended follow up.
    Arm type
    ILMA (reference)

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Intralesional macular atrophy (ILMA) present in study eye
    Arm description
    Intralesional macular atrophy (ILMA) present in study eye at extended follow up Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA)) during extended follow up.
    Arm type
    ILMA

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Geographic atrophy (GA) absent in study eye
    Arm description
    Geographic atrophy (GA) absent in study eye at extended follow up Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA)) during extended follow up.
    Arm type
    GA (reference)

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Geographic atrophy (GA) present in study eye
    Arm description
    Geographic atrophy (GA) present in study eye at extended follow up Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA)) during extended follow up.
    Arm type
    GA

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Developed/worsened intralesional macular atrophy (ILMA)
    Arm description
    Defined as the development (incident) or expansion of the area (worsened) of ILMA. Expansion of the area of ILMA was quantified and was classified as worsened when it increased by >20%
    Arm type
    ILMA

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Did not develop/worsen intralesional macular atrophy (ILMA)
    Arm description
    Defined as the development (incident) or expansion of the area (worsened) of ILMA. Expansion of the area of ILMA was quantified and was classified as worsened when it increased by >20%
    Arm type
    ILMA

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Developed/worsend geographic atrophy (GA)
    Arm description
    Defined as the development (incident) or expansion of the area (worsened) of GA. Expansion of the area of GA was quantified and was classified as worsened when it increased by >20%.
    Arm type
    GA

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Did not develop/worsen geographic atrophy (GA)
    Arm description
    Defined as the development (incident) or expansion of the area (worsened) of GA. Expansion of the area of GA was quantified and was classified as worsened when it increased by >20%.
    Arm type
    GA

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Follow-up cohort IVAN randomised allocation: Ranibizumab IVAN randomised allocation: Bevacizumab IVAN randomised allocation: Continuous IVAN randomised allocation: Discontinuous Intralesional macular atrophy (ILMA) absent in study eye Intralesional macular atrophy (ILMA) present in study eye Geographic atrophy (GA) absent in study eye Geographic atrophy (GA) present in study eye Developed/worsened intralesional macular atrophy (ILMA) Did not develop/worsen intralesional macular atrophy (ILMA) Developed/worsend geographic atrophy (GA) Did not develop/worsen geographic atrophy (GA)
    Started
    532
    272
    260
    269
    263
    122
    346
    309
    159
    243
    138
    142
    311
    Completed
    532
    272
    260
    269
    263
    122
    346
    309
    159
    243
    138
    142
    311

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Follow-up cohort
    Reporting group description
    -

    Reporting group values
    Follow-up cohort Total
    Number of subjects
    532 532
    Age categorical
    Age at IVAN exit
    Units: Subjects
        Adults (18-64 years)
    19 19
        From 65-84 years
    384 384
        85 years and over
    129 129
    Age continuous
    Age at IVAN exit
    Units: years
        arithmetic mean (standard deviation)
    79.4 ± 7.4 -
    Gender categorical
    Units: Subjects
        Female
    320 320
        Male
    212 212
    Drug
    Drug allocation during IVAN trial
    Units: Subjects
        Ranibizumab
    272 272
        Bevacizumab
    260 260
    Drug frequency
    Treatment regimen during IVAN trial
    Units: Subjects
        Continuous
    269 269
        Discontinuous
    263 263
    Angina at IVAN entry
    Units: Subjects
        Yes
    72 72
        No
    460 460
    Dyspnoea at IVAN entry
    Units: Subjects
        Yes
    97 97
        No
    433 433
        Missing
    2 2
    Dyspnoea at IVAN exit
    Units: Subjects
        Yes
    106 106
        No
    424 424
        Missing
    2 2
    Myocardial infarction at IVAN entry
    Units: Subjects
        Yes
    37 37
        No
    495 495
    Transient ischemic attack at IVAN entry
    Units: Subjects
        Yes
    26 26
        No
    477 477
        Missing
    29 29
    Stroke at IVAN entry
    Units: Subjects
        Yes
    8 8
        No
    524 524
    DVT/PE at IVAN entry
    DVT = deep vein thrombosis; PE =pulmonary embolism
    Units: Subjects
        Yes
    30 30
        No
    501 501
        Missing
    1 1
    Current or past smoker at IVAN entry
    Units: Subjects
        Yes
    331 331
        No
    197 197
        Missing
    4 4
    Systolic BP at IVAN entry
    BP = Blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    142.4 ± 19.2 -
    Diastolic BP at IVAN entry
    BP = Blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    77.0 ± 10.2 -
    Systolic BP at IVAN exit
    BP = Blood pressure Data missing for 8 patients (3 Attenders, 1 Survivor, passive data collection only, 4 Deceased, passive data collection only)
    Units: mmHG
        arithmetic mean (standard deviation)
    138.5 ± 18.9 -
    Diastolic BP at IVAN exit
    BP = Blood pressure Data missing for 8 patients (3 Attenders, 1 Survivor, passive data collection only, 4 Deceased, passive data collection only)
    Units: mmHg
        arithmetic mean (standard deviation)
    74.3 ± 10.2 -
    Subject analysis sets

    Subject analysis set title
    Attenders
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who attended a research visit as part of the IVAN follow-up study. 196/199 (98.5%) have at least one ophthalmology appointment as part of usual care since IVAN exit Length of follow up during usual care since IVAN entry (years, Median IQR): 6.8 (6.1, 7.4) Length of follow up during usual care since IVAN exit (years, Median IQR): 4.8 (4.2, 5.4) Length of follow up to research appointment since IVAN entry (years, Median IQR): 7.3 (6.8, 7.8) Length of follow up to research appointment since IVAN exit (years, Median IQR): 5.3 (4.8, 5.8)

    Subject analysis set title
    Survivor, passive data collection only
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Non-attenders (passive data collection only) - survivors 198/209 (94.7%) have at least one ophthalmology appointment as part of usual care since IVAN exit Length of follow up during usual care since IVAN entry (years, Median IQR): 6.3 (4.3, 7.4) Length of follow up during usual care since IVAN exit (years, Median IQR): 4.4 (2.3, 5.4)

    Subject analysis set title
    Deceased, passive data collection only
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Non-attenders (passive data collection only) - deceased 112/124 (90.3%) have at least one ophthalmology appointment as part of usual care since IVAN exit Length of follow up during usual care since IVAN entry (years, Median IQR): 3.8 (3.0, 4.8) Length of follow up during usual care since IVAN exit (years, Median IQR): 1.7 (1.1, 2.8)

    Subject analysis sets values
    Attenders Survivor, passive data collection only Deceased, passive data collection only
    Number of subjects
    199
    209
    124
    Age categorical
    Age at IVAN exit
    Units: Subjects
        Adults (18-64 years)
    9
    10
    0
        From 65-84 years
    166
    144
    74
        85 years and over
    24
    55
    50
    Age continuous
    Age at IVAN exit
    Units: years
        arithmetic mean (standard deviation)
    76.5 ± 7.0
    79.6 ± 7.5
    83.8 ± 5.4
    Gender categorical
    Units: Subjects
        Female
    114
    138
    68
        Male
    85
    71
    56
    Drug
    Drug allocation during IVAN trial
    Units: Subjects
        Ranibizumab
    105
    105
    62
        Bevacizumab
    94
    104
    62
    Drug frequency
    Treatment regimen during IVAN trial
    Units: Subjects
        Continuous
    101
    103
    65
        Discontinuous
    98
    106
    59
    Angina at IVAN entry
    Units: Subjects
        Yes
    19
    25
    28
        No
    180
    184
    96
    Dyspnoea at IVAN entry
    Units: Subjects
        Yes
    25
    39
    33
        No
    173
    169
    91
        Missing
    1
    1
    0
    Dyspnoea at IVAN exit
    Units: Subjects
        Yes
    31
    41
    34
        No
    168
    168
    88
        Missing
    0
    0
    2
    Myocardial infarction at IVAN entry
    Units: Subjects
        Yes
    7
    14
    16
        No
    192
    195
    108
    Transient ischemic attack at IVAN entry
    Units: Subjects
        Yes
    7
    11
    8
        No
    180
    188
    109
        Missing
    12
    10
    7
    Stroke at IVAN entry
    Units: Subjects
        Yes
    3
    2
    3
        No
    196
    207
    121
    DVT/PE at IVAN entry
    DVT = deep vein thrombosis; PE =pulmonary embolism
    Units: Subjects
        Yes
    8
    9
    13
        No
    191
    199
    111
        Missing
    0
    1
    0
    Current or past smoker at IVAN entry
    Units: Subjects
        Yes
    113
    128
    90
        No
    83
    81
    33
        Missing
    3
    0
    1
    Systolic BP at IVAN entry
    BP = Blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    140.6 ± 17.7
    143.1 ± 19.6
    144.0 ± 20.7
    Diastolic BP at IVAN entry
    BP = Blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    76.7 ± 9.0
    78.3 ± 10.3
    75.0 ± 11.6
    Systolic BP at IVAN exit
    BP = Blood pressure Data missing for 8 patients (3 Attenders, 1 Survivor, passive data collection only, 4 Deceased, passive data collection only)
    Units: mmHG
        arithmetic mean (standard deviation)
    137.3 ± 17.2
    140.2 ± 18.9
    137.6 ± 21.5
    Diastolic BP at IVAN exit
    BP = Blood pressure Data missing for 8 patients (3 Attenders, 1 Survivor, passive data collection only, 4 Deceased, passive data collection only)
    Units: mmHg
        arithmetic mean (standard deviation)
    75.4 ± 9.3
    74.9 ± 10.4
    71.6 ± 10.9

    End points

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    End points reporting groups
    Reporting group title
    Follow-up cohort
    Reporting group description
    All participants in the extended follow-up study Of the 532 participants in the extended follow-up study, 124 had died and 199 agreed to attend a specific research visit. Data were collected passively for non-attenders (124 deceased patients and 209 who did not wish to attend a research visit)

    Reporting group title
    IVAN randomised allocation: Ranibizumab
    Reporting group description
    This is an observational follow up of the original participants who were enrolled in the IVAN trial. The participants were initially randomised to one of four treatment regimens in the original IVAN trial and after exiting the trial, participants were treated in the NHS. The follow up study looked at the long term outcomes of these patients and is purely observational in that there was data collection but no intervention. This arm is the treatment allocation of the original IVAN trial.

    Reporting group title
    IVAN randomised allocation: Bevacizumab
    Reporting group description
    This is an observational follow up of the original participants who were enrolled in the IVAN trial. The participants were initially randomised to one of four treatment regimens in the original IVAN trial and after exiting the trial, participants were treated in the NHS. The follow up study looked at the long term outcomes of these patients and is purely observational in that there was data collection but no intervention. This arm is the treatment allocation of the original IVAN trial.

    Reporting group title
    IVAN randomised allocation: Continuous
    Reporting group description
    This is an observational follow up of the original participants who were enrolled in the IVAN trial. The participants were initially randomised to one of four treatment regimens in the original IVAN trial and after exiting the trial, participants were treated in the NHS. The follow up study looked at the long term outcomes of these patients and is purely observational in that there was data collection but no intervention. This arm is the treatment allocation of the original IVAN trial.

    Reporting group title
    IVAN randomised allocation: Discontinuous
    Reporting group description
    This is an observational follow up of the original participants who were enrolled in the IVAN trial. The participants were initially randomised to one of four treatment regimens in the original IVAN trial and after exiting the trial, participants were treated in the NHS. The follow up study looked at the long term outcomes of these patients and is purely observational in that there was data collection but no intervention. This arm is the treatment allocation of the original IVAN trial.

    Reporting group title
    Intralesional macular atrophy (ILMA) absent in study eye
    Reporting group description
    Intralesional macular atrophy (ILMA) absent in study eye at extended follow up. Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA)) during extended follow up.

    Reporting group title
    Intralesional macular atrophy (ILMA) present in study eye
    Reporting group description
    Intralesional macular atrophy (ILMA) present in study eye at extended follow up Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA)) during extended follow up.

    Reporting group title
    Geographic atrophy (GA) absent in study eye
    Reporting group description
    Geographic atrophy (GA) absent in study eye at extended follow up Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA)) during extended follow up.

    Reporting group title
    Geographic atrophy (GA) present in study eye
    Reporting group description
    Geographic atrophy (GA) present in study eye at extended follow up Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA)) during extended follow up.

    Reporting group title
    Developed/worsened intralesional macular atrophy (ILMA)
    Reporting group description
    Defined as the development (incident) or expansion of the area (worsened) of ILMA. Expansion of the area of ILMA was quantified and was classified as worsened when it increased by >20%

    Reporting group title
    Did not develop/worsen intralesional macular atrophy (ILMA)
    Reporting group description
    Defined as the development (incident) or expansion of the area (worsened) of ILMA. Expansion of the area of ILMA was quantified and was classified as worsened when it increased by >20%

    Reporting group title
    Developed/worsend geographic atrophy (GA)
    Reporting group description
    Defined as the development (incident) or expansion of the area (worsened) of GA. Expansion of the area of GA was quantified and was classified as worsened when it increased by >20%.

    Reporting group title
    Did not develop/worsen geographic atrophy (GA)
    Reporting group description
    Defined as the development (incident) or expansion of the area (worsened) of GA. Expansion of the area of GA was quantified and was classified as worsened when it increased by >20%.

    Subject analysis set title
    Attenders
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who attended a research visit as part of the IVAN follow-up study. 196/199 (98.5%) have at least one ophthalmology appointment as part of usual care since IVAN exit Length of follow up during usual care since IVAN entry (years, Median IQR): 6.8 (6.1, 7.4) Length of follow up during usual care since IVAN exit (years, Median IQR): 4.8 (4.2, 5.4) Length of follow up to research appointment since IVAN entry (years, Median IQR): 7.3 (6.8, 7.8) Length of follow up to research appointment since IVAN exit (years, Median IQR): 5.3 (4.8, 5.8)

    Subject analysis set title
    Survivor, passive data collection only
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Non-attenders (passive data collection only) - survivors 198/209 (94.7%) have at least one ophthalmology appointment as part of usual care since IVAN exit Length of follow up during usual care since IVAN entry (years, Median IQR): 6.3 (4.3, 7.4) Length of follow up during usual care since IVAN exit (years, Median IQR): 4.4 (2.3, 5.4)

    Subject analysis set title
    Deceased, passive data collection only
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Non-attenders (passive data collection only) - deceased 112/124 (90.3%) have at least one ophthalmology appointment as part of usual care since IVAN exit Length of follow up during usual care since IVAN entry (years, Median IQR): 3.8 (3.0, 4.8) Length of follow up during usual care since IVAN exit (years, Median IQR): 1.7 (1.1, 2.8)

    Primary: Development of intralesional macular atrophy (ILMA)

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    End point title
    Development of intralesional macular atrophy (ILMA)
    End point description
    ILMA = intralesional macular atrophy (defined as atrophy lying within the footprint of the neovascular lesion); Primary morphology outcome Study eyes with ILMA at IVAN exit (baseline) were excluded from this analysis. Missing data imputed using multiple imputation methods. We had intended to examine the impact of HRM type (well or ill defined). However, review of the OCT data did not support dichotomising participant eyes based on HRM. HRM was therefore modelled as present vs. absent. ILMA= Intralesional macular atrophy, GA= Geographic atrophy, FU=Follow up, CNV= Choroidal neovascularisation, HRM= Hyperreflective material, PED= Pigment Epithelial Detachment, SRF= Subretinal fluid, nAMD= neovascular age-related macular degeneration, CI=Confidence interval
    End point type
    Primary
    End point timeframe
    Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA))
    End point values
    Follow-up cohort IVAN randomised allocation: Ranibizumab IVAN randomised allocation: Bevacizumab IVAN randomised allocation: Continuous IVAN randomised allocation: Discontinuous Intralesional macular atrophy (ILMA) absent in study eye Intralesional macular atrophy (ILMA) present in study eye Geographic atrophy (GA) absent in study eye Geographic atrophy (GA) present in study eye Developed/worsened intralesional macular atrophy (ILMA) Did not develop/worsen intralesional macular atrophy (ILMA) Developed/worsend geographic atrophy (GA) Did not develop/worsen geographic atrophy (GA)
    Number of subjects analysed
    319 [1]
    167 [2]
    152 [3]
    157 [4]
    162 [5]
    122
    197 [6]
    225 [7]
    94 [8]
    197 [9]
    122 [10]
    84 [11]
    225 [12]
    Units: Patients
        Developed ILMA
    197
    101
    96
    59
    63
    0
    197
    109
    88
    197
    0
    78
    109
        Did not develop ILMA
    122
    66
    56
    59
    63
    122
    0
    116
    6
    0
    122
    6
    116
    Notes
    [1] - Exclusions: a) No images available (n=64). b) ILMA at baseline (n=149).
    [2] - Exclusions: a) No images available (n=27). b) ILMA at baseline (n=78).
    [3] - Exclusions: a) No images available (n=37). b) ILMA at baseline (n=71).
    [4] - Exclusions: a) No images available (n=35). b) ILMA at baseline (n=77).
    [5] - Exclusions: a) No images available (n=29). b) ILMA at baseline (n=72).
    [6] - Exclusions: ILMA at baseline (n=149)
    [7] - Exclusions: a) ILMA at baseline (n=84).
    [8] - Exclusions: a) ILMA at baseline (n=65).
    [9] - Exclusions: a) ILMA at baseline (n=46).
    [10] - Exclusions: a) ILMA at baseline (n=16).
    [11] - Exclusions: a) ILMA at baseline (n=58).
    [12] - Exclusions: a) ILMA at baseline (n=86).
    Statistical analysis title
    Effect of age at IVAN exit (per 10 years)
    Statistical analysis description
    Multivariable model adjusted for: Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    2.62
    Statistical analysis title
    Effect of gender (male)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.3
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    1.28
    Statistical analysis title
    Effect of IVAN trial drug allocation (Bevacizumab)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) present in study eye v Intralesional macular atrophy (ILMA) absent in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.519
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.98
    Statistical analysis title
    Effect of IVAN trial treatment regimen (Discont.)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug allocation during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.879
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.61
    Statistical analysis title
    Effect of injection rate during EFU (per year)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) present in study eye v Intralesional macular atrophy (ILMA) absent in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.021
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    0.98
    Statistical analysis title
    Effect of >50% classic CNV at IVAN entry
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.173
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.36
         upper limit
    1.2
    Statistical analysis title
    Effect of retinal thickness at IVAN exit(per 10µm)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10mm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.068
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    2.07
    Statistical analysis title
    Effect of subretinal fluid (SRF) at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.676
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.6
    Statistical analysis title
    Effect of PED at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.359
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    1.6
    Statistical analysis title
    Effect of PED at EFU (at fovea height <85µm)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [13]
    P-value
    = 0.115 [14]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.75
    Notes
    [13] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [14] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of PED at EFU (absent at fovea)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [15]
    P-value
    = 0.115 [16]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.28
         upper limit
    5.14
    Notes
    [15] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [16] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of PED at EFU (absent)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) present in study eye v Intralesional macular atrophy (ILMA) absent in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [17]
    P-value
    = 0.115 [18]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    5.37
    Notes
    [17] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [18] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of HRM at EFU
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) present in study eye v Intralesional macular atrophy (ILMA) absent in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.833
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.99
    Statistical analysis title
    Effect of ILMA FE at IVAN exit (ILMA present)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [19]
    P-value
    = 0.937 [20]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    3.88
    Notes
    [19] - ILMA in FE at IVAN exit categorised: 1: nAMD lesion, ILMA absent (reference category) 2: nAMD lesion, ILMA present 2: No nAMD lesion
    [20] - p-value is for overall effect of categorised ILMA in FE at IVAN exit
    Statistical analysis title
    Effect of ILMA FE at IVAN exit (no nAMD lesion)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE GA in FE at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [21]
    P-value
    = 0.937 [22]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.8
    Notes
    [21] - ILMA in FE at IVAN exit categorised: 1: nAMD lesion, ILMA absent (reference category) 2: nAMD lesion, ILMA present 2: No nAMD lesion
    [22] - p-value is for overall effect of categorised ILMA in FE at IVAN exit
    Statistical analysis title
    Effect of GA in FE at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion)
    Comparison groups
    Intralesional macular atrophy (ILMA) present in study eye v Intralesional macular atrophy (ILMA) absent in study eye
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.106
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    9.91

    Primary: Final distance visual acuity (DVA) in study eye

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    End point title
    Final distance visual acuity (DVA) in study eye
    End point description
    DVA was the primary visual function outcome
    End point type
    Primary
    End point timeframe
    DVA in study eye (most recent reading during extended FU, including research appointment for attenders).
    End point values
    Follow-up cohort IVAN randomised allocation: Ranibizumab IVAN randomised allocation: Bevacizumab IVAN randomised allocation: Continuous IVAN randomised allocation: Discontinuous Intralesional macular atrophy (ILMA) absent in study eye Intralesional macular atrophy (ILMA) present in study eye Geographic atrophy (GA) absent in study eye Geographic atrophy (GA) present in study eye Developed/worsened intralesional macular atrophy (ILMA) Did not develop/worsen intralesional macular atrophy (ILMA) Developed/worsend geographic atrophy (GA) Did not develop/worsen geographic atrophy (GA)
    Number of subjects analysed
    508 [23]
    262 [24]
    246 [25]
    257 [26]
    251 [27]
    113 [28]
    315 [29]
    289 [30]
    139 [31]
    243
    138
    141 [32]
    310 [33]
    Units: Letters
        median (inter-quartile range (Q1-Q3))
    57 (29.5 to 71.5)
    57.5 (30.0 to 72.0)
    57.0 (28.0 to 71.0)
    53.0 (30.0 to 73.0)
    58.0 (29.0 to 70.0)
    66.3 (47.0 to 74.2)
    50.1 (27.6 to 67.6)
    60.9 (39.4 to 71.5)
    38.5 (24.3 to 64.4)
    52.0 (24.0 to 69.0)
    64.5 (36.0 to 76.0)
    41.0 (22.0 to 63.0)
    63.0 (34.0 to 73.0)
    Notes
    [23] - Exclusions: No VA reading since IVAN exit (n=24)
    [24] - Exclusions: No VA reading since IVAN exit (n=10)
    [25] - Exclusions: No VA reading since IVAN exit (n=14)
    [26] - Exclusions: No VA reading since IVAN exit (n=12)
    [27] - Exclusions: No VA reading since IVAN exit (n=12)
    [28] - Exclusions: Less than 5 VA readings since IVAN exit (n=9)
    [29] - Exclusions: Less than 5 VA readings since IVAN exit (n=31)
    [30] - Exclusions: Less than 5 VA readings since IVAN exit (n=20)
    [31] - Exclusions: Less than 5 VA readings since IVAN exit (n=20)
    [32] - Exclusions: No VA reading since IVAN exit (n=1)
    [33] - Exclusions: No VA reading since IVAN exit (n=1)
    Statistical analysis title
    Effect of trial drug allocation on DVA
    Statistical analysis description
    The effects of the randomized allocations on DVA in the study eye at the most recent recorded visit was assessed using linear regression. These analyses were adjusted for centre size (seven strata as per the IVAN trial). Excluding patients who do not have a DVA reading since IVAN exit (n=24)
    Comparison groups
    IVAN randomised allocation: Bevacizumab v IVAN randomised allocation: Ranibizumab
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.6429
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.5
         upper limit
    3.4
    Statistical analysis title
    Effect of trial treatment regimen on DVA
    Statistical analysis description
    The effects of the randomized allocations on DVA in the study eye at the most recent recorded visit was assessed using linear regression. These analyses were adjusted for centre size (seven strata as per the IVAN trial). Excluding patients who do not have a DVA reading since IVAN exit (24)
    Comparison groups
    IVAN randomised allocation: Continuous v IVAN randomised allocation: Discontinuous
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.9917
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.4
         upper limit
    4.4
    Statistical analysis title
    Effect of ILMA on DVA
    Statistical analysis description
    A linear random effects methods model was fitted to DVA readings between IVAN exit visit and the date of the image used to grade ILMA. From this model, participants' DVA values were predicted for the date of the image used to grade ILMA. A linear regression model was then fitted to estimate associations between the presence of ILMA on predicated DVA. Analyses were adjusted for visual function at IVAN exit. Excluding patients with no SE images (n=64) and patients with <5 DVA readings (n=40)
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.0206
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.2
         upper limit
    -0.8
    Statistical analysis title
    Effect of GA on DVA
    Statistical analysis description
    A linear random effects methods model was fitted to DVA readings between IVAN exit visit and the date of the image used to grade ILMA. From this model, participants' DVA values were predicted for the date of the image used to grade ILMA. A linear regression model was then fitted to estimate associations between the presence of ILMA on predicated DVA. Analyses were adjusted for visual function at IVAN exit. Excluding patients with no SE images (n=64) and patients with <5 DVA readings (n=40)
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.0179
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -5.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.5
         upper limit
    -0.9

    Primary: Survival

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    End point title
    Survival
    End point description
    Survival was the primary safety outcome
    End point type
    Primary
    End point timeframe
    Time to death since IVAN entry. Times were censored at most recent clinical review.
    End point values
    Follow-up cohort IVAN randomised allocation: Ranibizumab IVAN randomised allocation: Bevacizumab IVAN randomised allocation: Continuous IVAN randomised allocation: Discontinuous Intralesional macular atrophy (ILMA) absent in study eye Intralesional macular atrophy (ILMA) present in study eye Geographic atrophy (GA) absent in study eye Geographic atrophy (GA) present in study eye Developed/worsened intralesional macular atrophy (ILMA) Did not develop/worsen intralesional macular atrophy (ILMA) Developed/worsend geographic atrophy (GA) Did not develop/worsen geographic atrophy (GA)
    Number of subjects analysed
    532
    272
    260
    269
    263
    122
    346
    309
    159
    243
    138
    142
    311
    Units: Years
        median (inter-quartile range (Q1-Q3))
    6.2 (4.3 to 7.2)
    6.2 (4.4 to 7.2)
    6.2 (4.2 to 7.3)
    6.0 (4.3 to 7.1)
    6.4 (4.4 to 7.3)
    6.6 (4.7 to 7.3)
    6.3 (4.8 to 7.3)
    6.5 (5.0 to 7.3)
    6.1 (4.4 to 7.1)
    6.3 (5.1 to 7.3)
    6.6 (4.7 to 7.3)
    6.0 (4.4 to 7.0)
    6.5 (5.0 to 7.3)
    Statistical analysis title
    Effect of trial drug allocation on survival
    Statistical analysis description
    The effects of the randomized allocations on survival since IVAN entry was assessed using Cox proportional-hazards regression. These analyses were adjusted for centre size (seven strata as per the IVAN trial).
    Comparison groups
    IVAN randomised allocation: Ranibizumab v IVAN randomised allocation: Bevacizumab
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.3789
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.67
    Statistical analysis title
    Effect of trial treatment regimen on survival
    Statistical analysis description
    The effects of the randomized allocations on survival since IVAN entry was assessed using Cox proportional-hazards regression. These analyses were adjusted for centre size (seven strata as per the IVAN trial).
    Comparison groups
    IVAN randomised allocation: Continuous v IVAN randomised allocation: Discontinuous
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.5115
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    1.27

    Secondary: Development of geographic atrophy (GA)

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    End point title
    Development of geographic atrophy (GA)
    End point description
    GA = Geographic atrophy (defined as atrophy lying outside the footprint of the neovascular lesion) Study eyes with GA at IVAN exit (baseline) were excluded from this analysis. Missing data imputed using multiple imputation methods. ILMA= Intralesional macular atrophy, GA= Geographic atrophy, FU=Follow up, CNV= Choroidal neovascularisation, HRM= Hyperreflective material, PED= Pigment Epithelial Detachment, SRF= Subretinal fluid, nAMD= neovascular age-related macular degeneration, CI=Confidence interval
    End point type
    Secondary
    End point timeframe
    Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA))
    End point values
    Follow-up cohort IVAN randomised allocation: Ranibizumab IVAN randomised allocation: Bevacizumab IVAN randomised allocation: Continuous IVAN randomised allocation: Discontinuous Intralesional macular atrophy (ILMA) absent in study eye Intralesional macular atrophy (ILMA) present in study eye Geographic atrophy (GA) absent in study eye Geographic atrophy (GA) present in study eye Developed/worsened intralesional macular atrophy (ILMA) Did not develop/worsen intralesional macular atrophy (ILMA) Developed/worsend geographic atrophy (GA) Did not develop/worsen geographic atrophy (GA)
    Number of subjects analysed
    448 [34]
    233 [35]
    215 [36]
    223 [37]
    225 [38]
    122
    326 [39]
    309
    139 [40]
    229 [41]
    137 [42]
    139 [43]
    309 [44]
    Units: Patients
        Developed GA
    139
    78
    61
    62
    77
    6
    133
    0
    139
    87
    6
    139
    0
        Did not develop GA
    309
    155
    154
    161
    148
    116
    193
    309
    0
    142
    131
    0
    309
    Notes
    [34] - Exclusions: a) No images available (n=64). b) GA at baseline (n=20).
    [35] - Exclusions: a) No images available (n=27). b) GA at baseline (n=12).
    [36] - Exclusions: a) No images available (n=37). b) GA at baseline (n=8).
    [37] - Exclusions: a) No images available (n=35). b) GA at baseline (n=11).
    [38] - Exclusions: a) No images available (n=29). b) GA at baseline (n=9).
    [39] - Exclusions: a) GA at baseline (n=20).
    [40] - Exclusions: GA at baseline (n=20)
    [41] - Exclusions: a) GA at baseline (n=14).
    [42] - Exclusions: a) GA at baseline (n=1).
    [43] - Exclusions: a) GA at baseline (n=3).
    [44] - Exclusions: a) GA at baseline (n=2).
    Statistical analysis title
    Effect of age at IVAN exit (per 10 years)
    Statistical analysis description
    Multivariable model adjusted for: Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.49
         upper limit
    2.96
    Statistical analysis title
    Effect of gender (male)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.613
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.41
    Statistical analysis title
    Effect of IVAN trial drug allocation (Bevacizumab)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.136
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.12
    Statistical analysis title
    Effect of IVAN trial treatment regimen (Discont.)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug alliocation during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.079
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.95
         upper limit
    2.37
    Statistical analysis title
    Effect of injection rate during EFU (per year)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.045
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    0.998
    Statistical analysis title
    Effect of >50% classic CNV at IVAN entry
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.518
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    2.06
    Statistical analysis title
    Effect of retinal thickness at IVAN exit(per 10µm)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.318
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.61
    Statistical analysis title
    Effect of subretinal fluid (SRF) at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) present in study eye v Geographic atrophy (GA) absent in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.67
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.57
    Statistical analysis title
    Effect of PED present at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.812
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    2.01
    Statistical analysis title
    Effect of PED at EFU (at fovea height <85µm)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [45]
    P-value
    = 0.003 [46]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    2.11
    Notes
    [45] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [46] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of PED at EFU (absent at fovea)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [47]
    P-value
    = 0.003 [48]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.51
         upper limit
    5.21
    Notes
    [47] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [48] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of PED at EFU (absent)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [49]
    P-value
    = 0.003 [50]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    6.46
    Notes
    [49] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [50] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of ILMA FE at IVAN exit (ILMA present)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [51]
    P-value
    = 0.974 [52]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    2.22
    Notes
    [51] - ILMA in FE at IVAN exit categorised: 1: nAMD lesion, ILMA absent (reference category) 2: nAMD lesion, ILMA present 2: No nAMD lesion
    [52] - p-value is for overall effect of categorised ILMA in FE at IVAN exit
    Statistical analysis title
    Effect of ILMA FE at IVAN exit (no nAMD lesion)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) GA in FE at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [53]
    P-value
    = 0.974 [54]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    1.62
    Notes
    [53] - ILMA in FE at IVAN exit categorised: 1: nAMD lesion, ILMA absent (reference category) 2: nAMD lesion, ILMA present 2: No nAMD lesion
    [54] - p-value is for overall effect of categorised ILMA in FE at IVAN exit
    Statistical analysis title
    Effect of GA in FE at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion)
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.56
         upper limit
    6.32

    Secondary: Development/worsening of intralesional macular atrophy (ILMA)

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    End point title
    Development/worsening of intralesional macular atrophy (ILMA)
    End point description
    ILMA = intralesional macular atrophy (defined as atrophy lying within the footprint of the neovascular lesion) This outcome was defined as the development (incident) or expansion of the area (worsened) of ILMA. Expansion of the area of ILMA was quantified and was classified as worsened when it increased by >20%. The outcome was defined to include worsening of ILMA so that the analyses did not exclude study eyes with ILMA at baseline. Missing data imputed using multiple imputation methods. We had intended to examine the impact of HRM type (well or ill defined). However, review of the OCT data did not support dichotomising participant eyes based on HRM. HRM was therefore modelled as present vs. absent. ILMA= Intralesional macular atrophy, GA= Geographic atrophy, FU=Follow up, CNV= Choroidal neovascularisation, HRM= Hyperreflective material, PED= Pigment Epithelial Detachment, SRF= Subretinal fluid, nAMD= neovascular age-related macular degeneration, CI=Confidence interval
    End point type
    Secondary
    End point timeframe
    Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA))
    End point values
    Follow-up cohort IVAN randomised allocation: Ranibizumab IVAN randomised allocation: Bevacizumab IVAN randomised allocation: Continuous IVAN randomised allocation: Discontinuous Intralesional macular atrophy (ILMA) absent in study eye Intralesional macular atrophy (ILMA) present in study eye Geographic atrophy (GA) absent in study eye Geographic atrophy (GA) present in study eye Developed/worsened intralesional macular atrophy (ILMA) Did not develop/worsen intralesional macular atrophy (ILMA) Developed/worsend geographic atrophy (GA) Did not develop/worsen geographic atrophy (GA)
    Number of subjects analysed
    381 [55]
    204 [56]
    177 [57]
    187 [58]
    194 [59]
    122
    259 [60]
    273 [61]
    108 [62]
    243
    138
    96 [63]
    275 [64]
    Units: Patients
        Developed/worsened
    243
    130
    113
    120
    123
    0
    243
    142
    101
    243
    0
    89
    144
        Did not develop/worsen
    138
    74
    64
    67
    71
    122
    16
    131
    7
    0
    138
    7
    131
    Notes
    [55] - Exclusions: No images available since IVAN exit (n=64). Worsening unknown (n=87)
    [56] - Exclusions: No images available since IVAN exit (n=27). Worsening unknown (n=41)
    [57] - Exclusions: No images available since IVAN exit (n=37). Worsening unknown (n=46)
    [58] - Exclusions: No images available since IVAN exit (n=35). Worsening unknown (n=47)
    [59] - Exclusions: No images available since IVAN exit (n=29). Worsening unknown (n=40)
    [60] - Exclusions: Worsening unknown (n=87)
    [61] - Exclusions: Worsening unknown (n=36)
    [62] - Exclusions: Worsening unknown (n=51)
    [63] - Exclusions: Worsening unknown (n=46)
    [64] - Exclusions: Worsening unknown (n=36)
    Statistical analysis title
    Effect of age at IVAN exit (per 10 years)
    Statistical analysis description
    Multivariable model adjusted for: Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.28
         upper limit
    2.36
    Statistical analysis title
    Effect of gender (male)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.432
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.31
    Statistical analysis title
    Effect of IVAN trial drug allocation (Bevacizumab)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.539
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    1.82
    Statistical analysis title
    Effect of IVAN trial treatment regimen (Discont.)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug allocation during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.872
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    1.67
    Statistical analysis title
    Effect of injection rate during EFU (per year)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.089
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.01
    Statistical analysis title
    Effect of >50% classic CNV at IVAN entry
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.13
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    1.12
    Statistical analysis title
    Effect of retinal thickness at IVAN exit(per 10µm)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.311
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.61
    Statistical analysis title
    Effect of subretinal fluid (SRF) at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.497
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.43
    Statistical analysis title
    Effect of PED at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.835
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.86
    Statistical analysis title
    Effect of PED at EFU (at fovea height <85µm)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [65]
    P-value
    = 0.115 [66]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.81
    Notes
    [65] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [66] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of PED at EFU (absent at fovea)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [67]
    P-value
    = 0.115 [68]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.07
         upper limit
    3.54
    Notes
    [67] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [68] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of PED at EFU (absent)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [69]
    P-value
    = 0.115 [70]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    4.19
    Notes
    [69] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [70] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of HRM at EFU
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.625
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    2.16
    Statistical analysis title
    Effect of ILMA FE at IVAN exit (ILMA present)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [71]
    P-value
    = 0.937 [72]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    1.91
    Notes
    [71] - ILMA in FE at IVAN exit categorised: 1: nAMD lesion, ILMA absent (reference category) 2: nAMD lesion, ILMA present 2: No nAMD lesion
    [72] - p-value is for overall effect of categorised ILMA in FE at IVAN exit
    Statistical analysis title
    Effect of ILMA FE at IVAN exit (no nAMD lesion)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU GA in FE at IVAN exit
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [73]
    P-value
    = 0.937 [74]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.58
    Notes
    [73] - ILMA in FE at IVAN exit categorised: 1: nAMD lesion, ILMA absent (reference category) 2: nAMD lesion, ILMA present 2: No nAMD lesion
    [74] - p-value is for overall effect of categorised ILMA in FE at IVAN exit
    Statistical analysis title
    Effect of GA in FE at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) HRM present at EFU ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion)
    Comparison groups
    Developed/worsened intralesional macular atrophy (ILMA) v Did not develop/worsen intralesional macular atrophy (ILMA)
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.325
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    3.84

    Secondary: Development/worsening of geographic atrophy (GA)

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    End point title
    Development/worsening of geographic atrophy (GA)
    End point description
    GA = Geographic atrophy (defined as atrophy lying outside the footprint of the neovascular lesion) This outcome was defined as the development (incident) or expansion of the area (worsened) of GA. Expansion of the area of GA was quantified and was classified as worsened when it increased by >20%. The outcome was defined to include worsening of GA so that the analyses did not exclude study eyes with ILMA at baseline. Missing data imputed using multiple imputation methods. We had intended to examine the impact of HRM type (well or ill defined). However, review of the OCT data did not support dichotomising participant eyes based on HRM. HRM was therefore modelled as present vs. absent. ILMA= Intralesional macular atrophy, GA= Geographic atrophy, FU=Follow up, CNV= Choroidal neovascularisation, HRM= Hyperreflective material, PED= Pigment Epithelial Detachment, SRF= Subretinal fluid, nAMD= neovascular age-related macular degeneration, CI=Confidence interval
    End point type
    Secondary
    End point timeframe
    Determined using most recent image available (color fundus photography, blue light autofluorescence (AF), optical coherence tomography (OCT) or dye angiography fluorescein/indocyanine green (FFA))
    End point values
    Follow-up cohort IVAN randomised allocation: Ranibizumab IVAN randomised allocation: Bevacizumab IVAN randomised allocation: Continuous IVAN randomised allocation: Discontinuous Intralesional macular atrophy (ILMA) absent in study eye Intralesional macular atrophy (ILMA) present in study eye Geographic atrophy (GA) absent in study eye Geographic atrophy (GA) present in study eye Developed/worsened intralesional macular atrophy (ILMA) Did not develop/worsen intralesional macular atrophy (ILMA) Developed/worsend geographic atrophy (GA) Did not develop/worsen geographic atrophy (GA)
    Number of subjects analysed
    453 [75]
    236 [76]
    217 [77]
    226 [78]
    227 [79]
    122
    331 [80]
    309
    144 [81]
    233 [82]
    138
    142
    311
    Units: Patients
        Developed/worsened
    142
    79
    63
    64
    78
    6
    136
    0
    142
    89
    7
    142
    0
        Did not develop/worsen
    311
    157
    154
    162
    149
    116
    195
    309
    2
    144
    131
    0
    311
    Notes
    [75] - Exclusions: No images available since IVAN exit (n=64). Worsening unknown (n=15)
    [76] - Exclusions: No images available since IVAN exit (n=27). Worsening unknown (n=9)
    [77] - Exclusions: No images available since IVAN exit (n=37). Worsening unknown (n=6)
    [78] - Exclusions: No images available since IVAN exit (n=35). Worsening unknown (n=8)
    [79] - Exclusions: No images available since IVAN exit (n=29). Worsening unknown (n=7)
    [80] - Exclusions: Worsening unknown (n=15)
    [81] - Exclusions: Worsening unknown (n=15)
    [82] - Exclusions: Worsening unknown (n=10)
    Statistical analysis title
    Effect of age at IVAN exit (per 10 years)
    Statistical analysis description
    Multivariable model adjusted for: Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.44
         upper limit
    2.83
    Statistical analysis title
    Effect of gender (male)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.77
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    1.48
    Statistical analysis title
    Effect of IVAN trial drug allocation (Bevacizumab)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.233
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.19
    Statistical analysis title
    Effect of IVAN trial treatment regimen (Discont.)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug allocation during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.098
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.93
         upper limit
    2.27
    Statistical analysis title
    Effect of injection rate during EFU (per year)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Did not develop/worsen geographic atrophy (GA) v Developed/worsend geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.067
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1
    Statistical analysis title
    Effect of age >50% classic CNV at IVAN entry
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.448
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    2.05
    Statistical analysis title
    Effect of retinal thickness at IVAN exit(per 10µm)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.316
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.6
    Statistical analysis title
    Effect of subretinal fluid (SRF) at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.517
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    1.46
    Statistical analysis title
    Effect of PED present at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.886
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    1.9
    Statistical analysis title
    Effect of PED at EFU (at fovea height <85µm)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [83]
    P-value
    = 0.003 [84]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    2.03
    Notes
    [83] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [84] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of PED at EFU (absent at fovea)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [85]
    P-value
    = 0.003 [86]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.41
         upper limit
    4.69
    Notes
    [85] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [86] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of PED at EFU (absent)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [87]
    P-value
    = 0.003 [88]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    6.04
    Notes
    [87] - PED categorised: 1: Present at fovea height ≥ 85µm (Reference category) 2: Present at fovea height <85µm 3: Absent at fovea 4: PED absent
    [88] - p-value is for overall effect of categorised PED at EFU
    Statistical analysis title
    Effect of ILMA FE at IVAN exit (ILMA present)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [89]
    P-value
    = 0.974 [90]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    2.24
    Notes
    [89] - ILMA in FE at IVAN exit categorised: 1: nAMD lesion, ILMA absent (reference category) 2: nAMD lesion, ILMA present 2: No nAMD lesion
    [90] - p-value is for overall effect of categorised ILMA in FE at IVAN exit
    Statistical analysis title
    Effect of ILMA FE at IVAN exit (no nAMD lesion)
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) GA in FE at IVAN exit
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [91]
    P-value
    = 0.974 [92]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.67
    Notes
    [91] - ILMA in FE at IVAN exit categorised: 1: nAMD lesion, ILMA absent (reference category) 2: nAMD lesion, ILMA present 2: No nAMD lesion
    [92] - p-value is for overall effect of categorised ILMA in FE at IVAN exit
    Statistical analysis title
    Effect of GA in FE at IVAN exit
    Statistical analysis description
    Multivariable model adjusted for: Age at IVAN exit (per 10 years) Gender Drug and treatment regimen during IVAN trial Injection rate during EFU (per year) >50% classic CNV at IVAN entry Retinal thickness at IVAN exit (per 10µm) SRF present at IVAN exit PED present at IVAN exit PED at EFU (at fovea: height ≥ 85µm, <85µm, PED absent at fovea, PED absent) ILMA at IVAN exit in FE (nAMD lesion ILMA absent, nAMD lesion ILMA present, No nAMD lesion)
    Comparison groups
    Developed/worsend geographic atrophy (GA) v Did not develop/worsen geographic atrophy (GA)
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.006
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.29
         upper limit
    4.76

    Secondary: Low luminance acuity (LLA) in study eye

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    End point title
    Low luminance acuity (LLA) in study eye
    End point description
    The association between IVAN treatment allocations and ILMA/GA and LLA was estimated only for attenders because LLA was only measured at the additional research visit. LLA was also not measured during the IVAN trial and therefore these models were not adjusted for baseline values. Sensitivity analyses adjusted for BCVA at IVAN exit visit.
    End point type
    Secondary
    End point timeframe
    Extended follow-up clinic appointment
    End point values
    Follow-up cohort IVAN randomised allocation: Ranibizumab IVAN randomised allocation: Bevacizumab IVAN randomised allocation: Continuous IVAN randomised allocation: Discontinuous Intralesional macular atrophy (ILMA) absent in study eye Intralesional macular atrophy (ILMA) present in study eye Geographic atrophy (GA) absent in study eye Geographic atrophy (GA) present in study eye Developed/worsened intralesional macular atrophy (ILMA) Did not develop/worsen intralesional macular atrophy (ILMA) Developed/worsend geographic atrophy (GA) Did not develop/worsen geographic atrophy (GA)
    Number of subjects analysed
    199 [93]
    105 [94]
    94 [95]
    101 [96]
    98 [97]
    86 [98]
    113 [99]
    165 [100]
    34 [101]
    93 [102]
    98 [103]
    28 [104]
    167 [105]
    Units: Letters
        median (inter-quartile range (Q1-Q3))
    38.0 (17.0 to 56.0)
    40.0 (18.0 to 56.0)
    30.5 (13.0 to 55.0)
    31.0 (15.0 to 56.0)
    44.0 (20.0 to 55.0)
    53.5 (26.0 to 61.0)
    27.0 (13.0 to 50.0)
    43.0 (20.0 to 57.0)
    12.0 (4.0 to 29.0)
    27.0 (13.0 to 51.0)
    50.5 (26.0 to 60.0)
    12.0 (4.0 to 27.5)
    43.0 (20.0 to 57.0)
    Notes
    [93] - Attenders only
    [94] - Attenders only
    [95] - Attenders only
    [96] - Attenders only
    [97] - Attenders only
    [98] - Attenders only
    [99] - Attenders only
    [100] - Attenders only
    [101] - Attenders only
    [102] - Attenders only
    [103] - Attenders only
    [104] - Attenders only
    [105] - Attenders only
    Statistical analysis title
    Effect of ILMA on LLA
    Statistical analysis description
    Linear regression was used to analyse the effect of ILMA in study eyes on low luminance visual acuity at extended follow-up.
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.001
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -15.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.6
         upper limit
    -9.4
    Statistical analysis title
    Effect of GA on LLA
    Statistical analysis description
    Linear regression was used to analyse the effect of GA in study eyes on low luminance visual acuity at extended follow-up.
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.001
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -18.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.6
         upper limit
    -10.4

    Secondary: Low luminance acuity (LLA) in study eye, adjusted for BCVA at IVAN exit (sensitivity analysis)

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    End point title
    Low luminance acuity (LLA) in study eye, adjusted for BCVA at IVAN exit (sensitivity analysis)
    End point description
    Sensitivity analyses adjusting for BCVA at IVAN exit visit.
    End point type
    Secondary
    End point timeframe
    Extended follow-up clinic appointment
    End point values
    Follow-up cohort IVAN randomised allocation: Ranibizumab IVAN randomised allocation: Bevacizumab IVAN randomised allocation: Continuous IVAN randomised allocation: Discontinuous Intralesional macular atrophy (ILMA) absent in study eye Intralesional macular atrophy (ILMA) present in study eye Geographic atrophy (GA) absent in study eye Geographic atrophy (GA) present in study eye Developed/worsened intralesional macular atrophy (ILMA) Did not develop/worsen intralesional macular atrophy (ILMA) Developed/worsend geographic atrophy (GA) Did not develop/worsen geographic atrophy (GA)
    Number of subjects analysed
    199 [106]
    105 [107]
    94 [108]
    101 [109]
    98 [110]
    86 [111]
    113 [112]
    165 [113]
    34 [114]
    93 [115]
    98 [116]
    28 [117]
    167 [118]
    Units: Letters
        median (inter-quartile range (Q1-Q3))
    38.0 (17.0 to 56.0)
    40.0 (18.0 to 56.0)
    30.5 (13.0 to 55.0)
    31.0 (15.0 to 56.0)
    44.0 (20.0 to 55.0)
    53.5 (26.0 to 61.0)
    27.0 (13.0 to 50.0)
    43.0 (20.0 to 57.0)
    12.0 (4.0 to 29.0)
    27.0 (13.0 to 51.0)
    50.5 (26.0 to 60.0)
    12.0 (4.0 to 27.5)
    43.0 (20.0 to 57.0)
    Notes
    [106] - Attenders only
    [107] - Attenders only
    [108] - Attenders only
    [109] - Attenders only
    [110] - Attenders only
    [111] - Attenders only
    [112] - Attenders only
    [113] - Attenders only
    [114] - Attenders only
    [115] - Attenders only
    [116] - Attenders only
    [117] - Attenders only
    [118] - Attenders only
    Statistical analysis title
    Effect of ILMA on LLA
    Statistical analysis description
    Linear regression was used to analyse the effect of ILMA in study eyes on low luminance visual acuity at extended follow-up; adjusting for BCVA at IVAN exit
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.001
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.7
         upper limit
    -5.3
    Statistical analysis title
    Effect of GA on LLA
    Statistical analysis description
    Linear regression was used to analyse the effect of ILMA in study eyes on low luminance visual acuity at extended follow-up; adjusting for BCVA at IVAN exit
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.001
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -17.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.4
         upper limit
    -10.1

    Secondary: Quality of life (EQ5D)

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    End point title
    Quality of life (EQ5D)
    End point description
    End point type
    Secondary
    End point timeframe
    This analysis was restricted to participants who were willing to compete the EQ-5D-5L and who had data at baseline and follow up.
    End point values
    Follow-up cohort IVAN randomised allocation: Ranibizumab IVAN randomised allocation: Bevacizumab IVAN randomised allocation: Continuous IVAN randomised allocation: Discontinuous Intralesional macular atrophy (ILMA) absent in study eye Intralesional macular atrophy (ILMA) present in study eye Geographic atrophy (GA) absent in study eye Geographic atrophy (GA) present in study eye Developed/worsened intralesional macular atrophy (ILMA) Did not develop/worsen intralesional macular atrophy (ILMA) Developed/worsend geographic atrophy (GA) Did not develop/worsen geographic atrophy (GA)
    Number of subjects analysed
    273 [119]
    147 [120]
    126 [121]
    139 [122]
    134 [123]
    95 [124]
    172 [125]
    203 [126]
    64 [127]
    133 [128]
    107 [129]
    53 [130]
    205 [131]
    Units: EQ5D state score
        median (inter-quartile range (Q1-Q3))
    0.8 (0.6 to 0.9)
    0.8 (0.6 to 0.9)
    0.8 (0.6 to 0.9)
    0.8 (0.6 to 0.9)
    0.8 (0.6 to 0.9)
    0.8 (0.7 to 1.0)
    0.7 (0.6 to 0.9)
    0.8 (0.6 to 0.9)
    0.7 (0.6 to 0.9)
    0.7 (0.6 to 0.9)
    0.8 (0.7 to 1.0)
    0.7 (0.6 to 1.0)
    0.8 (0.6 to 0.9)
    Notes
    [119] - Exclusions: Participants who did not opt to complete the questionnaire (n=259)
    [120] - Exclusions: Participants who did not opt to complete the questionnaire (n=125)
    [121] - Exclusions: Participants who did not opt to complete the questionnaire (n=134)
    [122] - Exclusions: Participants who did not opt to complete the questionnaire (n=130)
    [123] - Exclusions: Participants who did not opt to complete the questionnaire (n=129)
    [124] - Exclusions: Participants who did not opt to complete the questionnaire (n=27)
    [125] - Exclusions: Participants who did not opt to complete the questionnaire (n=174)
    [126] - Exclusions: Participants who did not opt to complete the questionnaire (n=106)
    [127] - Exclusions: Participants who did not opt to complete the questionnaire (n=95)
    [128] - Exclusions: Participants who did not opt to complete the questionnaire (n=110)
    [129] - Exclusions: Participants who did not opt to complete the questionnaire (n=31)
    [130] - Exclusions: Participants who did not opt to complete the questionnaire (n=89)
    [131] - Exclusions: Participants who did not opt to complete the questionnaire (n=106)
    Statistical analysis title
    Effect of trial drug allocation on EQ5D
    Statistical analysis description
    For EQ-5D-5L, no transformation could be applied to the data to satisfy the assumptions for linear regression. Therefore, the index score was categorised (EQ-5D-5L score, 1 (no problem in any dimension), 0.80 to 0.99 (a moderate problem in only one dimension), 0.5 to 0.79 (at least two moderate problems in any dimension) and <0.5 (at least one extreme problem)) and ordinal logistic regression was used. These analyses were adjusted for centre size (seven strata as per the IVAN trial).
    Comparison groups
    IVAN randomised allocation: Ranibizumab v IVAN randomised allocation: Bevacizumab
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.2419
    Method
    Regression, Logistic
    Parameter type
    Log odds ratio
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    2
    Statistical analysis title
    Effect of trial treatment regimen on EQ5D
    Statistical analysis description
    For EQ-5D-5L, no transformation could be applied to the data to satisfy the assumptions for linear regression. Therefore, the index score was categorised (EQ-5D-5L score, 1 (no problem in any dimension), 0.80 to 0.99 (a moderate problem in only one dimension), 0.5 to 0.79 (at least two moderate problems in any dimension) and <0.5 (at least one extreme problem)) and ordinal logistic regression was used. These analyses were adjusted for centre size (seven strata as per the IVAN trial).
    Comparison groups
    IVAN randomised allocation: Continuous v IVAN randomised allocation: Discontinuous
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.3887
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    1.3
    Statistical analysis title
    Effect of ILMA on EQ5D
    Statistical analysis description
    For EQ-5D-5L, no transformation could be applied to the data to satisfy the assumptions for linear regression. Therefore, the index score was categorised (EQ-5D-5L score, 1 (no problem in any dimension), 0.80 to 0.99 (a moderate problem in only one dimension), 0.5 to 0.79 (at least two moderate problems in any dimension) and <0.5 (at least one extreme problem)) and ordinal logistic regression was used. These analyses were adjusted for EQ5D score at IVAN exit.
    Comparison groups
    Intralesional macular atrophy (ILMA) absent in study eye v Intralesional macular atrophy (ILMA) present in study eye
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.0413
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    1
    Statistical analysis title
    Effect of GA on EQ5D
    Statistical analysis description
    For EQ-5D-5L, no transformation could be applied to the data to satisfy the assumptions for linear regression. Therefore, the index score was categorised (EQ-5D-5L score, 1 (no problem in any dimension), 0.80 to 0.99 (a moderate problem in only one dimension), 0.5 to 0.79 (at least two moderate problems in any dimension) and <0.5 (at least one extreme problem)) and ordinal logistic regression was used. These analyses were adjusted for EQ5D score at IVAN exit.
    Comparison groups
    Geographic atrophy (GA) absent in study eye v Geographic atrophy (GA) present in study eye
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.9794
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The AE reporting period for the study began upon completion of the consent form for the clinic appointment until the patient leaves the clinic appointment.
    Adverse event reporting additional description
    Only patients who attended a clinic appointment as part of the IVAN follow-up study are included in the adverse events reporting group. Adverse event that occurred during the clinic appointment were recorded. Any adverse events that occurred between the end of the IVAN trial and consent to the follow-up were considered medical history.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    N/A
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    Attenders
    Reporting group description
    -

    Serious adverse events
    Attenders
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 199 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Attenders
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 199 (0.50%)
    Eye disorders
    Vitreous floaters
    Additional description: This is almost certainly an event that occurred historically but which was noted at the research visit attended by the participant.
         subjects affected / exposed
    1 / 199 (0.50%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2015
    SUBSTANTIAL AMENDMENT 1: Section 8 of the protocol (safety reporting) was updated substantially in line with the Sponsor's policy and a table added detailing the terms and definitions of adverse events. New wording was inserted into section 4.4.2 on secondary outcomes explaining that Best Corrected Visual Acuity would be measured with both standard and low luminance visual acuity.
    08 Mar 2016
    SUBSTANTIAL AMENDMENT 2: Grounds of Non-Acceptance were received for protocol v5.0 from the MHRA therefore the safety sections were updated further in line with their recommendations and protocol v6.0 was submitted for approval.
    21 Mar 2016
    SUBSTANTIAL AMENDMENT 3: A change was made to the Patient Information Leaflet clarifying that research nurses could telephone participants if the reply slip had not been returned after two weeks. The change was made in response to feedback from research nurses and the Macular Disease Society highlighting the importance of verbal communication in this elderly, visually impaired group of participants.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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