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    Clinical Trial Results:
    A randomised controlled trial of standard and low dose Avastin® for Neovascular Macular Degeneration in the East Midlands

    Summary
    EudraCT number
    		 2009-014280-38
    Trial protocol
    		 GB  
    Global end of trial date
    31 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2019
    First version publication date
    04 Oct 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    09OY006
    Additional study identifiers
    ISRCTN number
    		 ISRCTN95654194
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Nottingham University Hospitals
    Sponsor organisation address
    Derby Road, Nottingham, United Kingdom, NG7 2UH
    Public contact
    R&I, Nottingham University Hospitals, 0044 0115 924 9924x6064, jennifer.boston@nuh.nhs.uk
    Scientific contact
    R&I, Nottingham University Hospitals, 0044 0115 924 9924x60645, jennifer.boston@nuh.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the relative effectiveness of standard versus low dose Avastin® (bevacizumab) for intravitreal injection on visual outcome in patients with nAMD.
    Protection of trial subjects
    None
    Background therapy
    		 None
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    01 Nov 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 812
    Worldwide total number of subjects
    812
    EEA total number of subjects
    812
    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)
    20
    From 65 to 84 years
    576
    85 years and over
    216

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants recruited from 5 UK (East Midlands) centres between November 2010 and March 2017.

    Pre-assignment
    Screening details
    		 Any patient eligible for anti-VEGF treatment in the NHS. The treating clinician will decide if the patient is likely to benefit.

    Pre-assignment period milestones
    Number of subjects started
    		 812
    Number of subjects completed
    		 812

    Period 1
    Period 1 title
    Visit A (baseline)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All but the pharmacist (who has no other role in the trial) are double blind to dose, but review schedule (revealed after induction) is not blinded (not possible to).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 L1 arm
    Arm description
    		 Low dose, monthly review
    Arm type
    		 Active comparator

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.625mg monthly (if required after first three injections)

    Arm title
    		 S1 arm
    Arm description
    		 Standard dose, monthly review
    Arm type
    		 Active comparator

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1.25mg monthly (if required after first three injections)

    Arm title
    		 L2 arm
    Arm description
    		 Low dose, bi-monthly review
    Arm type
    		 Active comparator

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.625mg monthly for first three injections, then bi-monthly if required

    Arm title
    		 S2 arm
    Arm description
    		 Standard dose, bi-monthly review
    Arm type
    		 Active comparator

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1.25mg monthly for first three injections, then bi-monthly if required

    Number of subjects in period 1
    		L1 arm S1 arm L2 arm S2 arm
    Started
    204
    203
    203
    202
    Completed
    204
    203
    203
    202
    Period 2
    Period 2 title
    Overall trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Dose was double blind to all but pharmacist, but review interview ("schedule") was not - not possible to blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 L1 - low dose monthly
    Arm description
    		 Low dose, monthly review
    Arm type
    		 Active comparator

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.625mg monthly (if required after first three injections)

    Arm title
    		 S1 - standard dose monthly
    Arm description
    		 Standard dose, monthly review
    Arm type
    		 Active comparator

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1.25mg monthly (if required after first three injections)

    Arm title
    		 L2 - low dose bi-monthly
    Arm description
    		 Low dose, bi-monthly review
    Arm type
    		 Active comparator

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.625mg monthly for first three injections, then bi-monthly if required

    Arm title
    		 S2 - standard dose bi-monthly
    Arm description
    		 Standard dose, bi-monthly review
    Arm type
    		 Active comparator

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1.25mg monthly for first three injections, then bi-monthly if required

    Number of subjects in period 2
    		L1 - low dose monthly S1 - standard dose monthly L2 - low dose bi-monthly S2 - standard dose bi-monthly
    Started
    204
    203
    203
    202
    Completed
    204
    203
    203
    202

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    L1 arm
    Reporting group description
    		 Low dose, monthly review

    Reporting group title
    S1 arm
    Reporting group description
    		 Standard dose, monthly review

    Reporting group title
    L2 arm
    Reporting group description
    		 Low dose, bi-monthly review

    Reporting group title
    S2 arm
    Reporting group description
    		 Standard dose, bi-monthly review

    Reporting group values
    		 L1 arm S1 arm L2 arm S2 arm Total
    Number of subjects
    		 204 203 203 202 812
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 8 6 4 2 20
        From 65-84 years
    		 150 143 144 139 576
        85 years and over
    		 46 54 55 61 216
    Age continuous
    Age at randomisation
    Units: years
        arithmetic mean (standard deviation)
    		 79 ± 7.5 80 ± 7.6 80 ± 7.4 81 ± 7.0 -
    Gender categorical
    Units: Subjects
        Female
    		 120 118 118 109 465
        Male
    		 84 85 85 93 347

    End points

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    End points reporting groups
    Reporting group title
    L1 arm
    Reporting group description
    		 Low dose, monthly review

    Reporting group title
    S1 arm
    Reporting group description
    		 Standard dose, monthly review

    Reporting group title
    L2 arm
    Reporting group description
    		 Low dose, bi-monthly review

    Reporting group title
    S2 arm
    Reporting group description
    		 Standard dose, bi-monthly review
    Reporting group title
    L1 - low dose monthly
    Reporting group description
    		 Low dose, monthly review

    Reporting group title
    S1 - standard dose monthly
    Reporting group description
    		 Standard dose, monthly review

    Reporting group title
    L2 - low dose bi-monthly
    Reporting group description
    		 Low dose, bi-monthly review

    Reporting group title
    S2 - standard dose bi-monthly
    Reporting group description
    		 Standard dose, bi-monthly review

    Primary: Visual deterioration (VD)

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    End point title
    		 Visual deterioration (VD)
    End point description
    An event is visual deterioration of >=15 letters during induction compared to baseline (visit A), or >=6 letters compared to mean baseline (mean over first 3 visits A-C). Those who do not have a visual deterioration while in the study are counted as censored at the point they exit, whatever the reason for exit (died, withdrawal of consent, stable disease, end of trial, exit for VD too small to qualify). Events are counted in both primary and fellow eyes.
    End point type
    Primary
    End point timeframe
    From randomisation (or start of treatment for late-joining fellow eyes), until exit from study.
    End point values
    		 L1 - low dose monthly S1 - standard dose monthly L2 - low dose bi-monthly S2 - standard dose bi-monthly
    Number of subjects analysed
    200 [1]
    200 [2]
    201 [3]
    200 [4]
    Units: event
    62
    61
    83
    77
    Notes
    [1] - 232 eyes (primary and fellow) analysed.
    [2] - 224 eyes (primary and fellow) analysed
    [3] - 223 eyes (primary and fellow) analysed
    [4] - 225 (primary and fellow) eyes analysed
    Statistical analysis title
    		 Cox regression analysis of primary outcome - dose
    Statistical analysis description
    Cox regression analysis of time to event (VD) with shared frailty (eyes), non-inferiority. Analysis according to randomised allocation. Adjustment for centre. No interaction between dose and schedule (review interval), hence main effects of dose and schedule used for estimation. Comparison of doses and schedules (monthly vs bi-monthly) are from same analysis, but presented separately due to limitations of EudraCT reporting system.
    Comparison groups
    L1 - low dose monthly v S1 - standard dose monthly v L2 - low dose bi-monthly v S2 - standard dose bi-monthly
    Number of subjects included in analysis
    801
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.42
    Notes
    [5] - Non-inferiority margin of 1.4. (upper 95% confidence interval for hazard ratio of less than 1.4 for non-inferiority). Comparison of dose ie (L1+L2) vs (S1+S2)
    Statistical analysis title
    		 Cox regression for primary outcome - schedule
    Statistical analysis description
    Cox regression analysis of time to event (VD) with shared frailty (eyes), non-inferiority. Analysis according to randomised allocation. Adjustment for centre. No interaction between dose and schedule (review interval), hence main effects of dose and schedule used for estimation. Comparison of doses and schedules (monthly vs bi-monthly) are from same analysis, but presented separately due to limitations of EudraCT reporting system.
    Comparison groups
    S1 - standard dose monthly v L2 - low dose bi-monthly v S2 - standard dose bi-monthly v L1 - low dose monthly
    Number of subjects included in analysis
    801
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 1.94
    Notes
    [6] - Non-inferiority margin of 1.4. (upper 95% confidence interval for hazard ratio of less than 1.4 for non-inferiority). Comparison of schedule (review interval) ie (L2+S2) vs (L1+S1)

    Secondary: Visual accuity (VA) at 9 months

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    End point title
    		 Visual accuity (VA) at 9 months
    End point description
    9 months from start of treatment with 10 week window either side. The VA reading within the window closest to 9 months will be used.
    End point type
    Secondary
    End point timeframe
    9 months from start of treatment
    End point values
    		 L1 - low dose monthly S1 - standard dose monthly L2 - low dose bi-monthly S2 - standard dose bi-monthly
    Number of subjects analysed
    200 [7]
    177 [8]
    182 [9]
    187 [10]
    Units: Letters read
        arithmetic mean (standard deviation)
    62.4 ± 16.9
    63.9 ± 16.3
    63.5 ± 14.2
    63.4 ± 15.2
    Notes
    [7] - eyes (primary and fellow). Not all have data within time window
    [8] - eyes (primary and fellow). Not all have data within time window.
    [9] - eyes (primary and fellow). Not all have data within window
    [10] - eyes (primary and fellow). Not all have eyes within window.
    Statistical analysis title
    		 VA at 9 months - comparison of dose
    Statistical analysis description
    Mixed effects model comparing VA (visual acuity) at 9 months between doses. The model is adjusted for baseline VA score and study centre. There was no evidence of interaction between dose and schedule (review interval) hence main effects are presented. Comparison of doses and schedules (monthly vs bi-monthly) are from same analysis, but presented separately due to limitations of EudraCT reporting system.
    Comparison groups
    L1 - low dose monthly v S1 - standard dose monthly v L2 - low dose bi-monthly v S2 - standard dose bi-monthly
    Number of subjects included in analysis
    746
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.08
         upper limit
    		 0.17
    Statistical analysis title
    		 VA at 9 months - comparison of schedule
    Statistical analysis description
    Mixed effects model comparing VA (visual acuity) at 9 months between schedules (monthly vs bi-monthly). The model is adjusted for baseline VA score and study centre. There was no evidence of interaction between dose and schedule (review interval) hence main effects are presented. Comparison of doses and schedules (monthly vs bi-monthly) are from same analysis, but presented separately due to limitations of EudraCT reporting system.
    Comparison groups
    L1 - low dose monthly v S1 - standard dose monthly v L2 - low dose bi-monthly v S2 - standard dose bi-monthly
    Number of subjects included in analysis
    746
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.99
         upper limit
    		 1.25

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomisation to exit from trial.
    Adverse event reporting additional description
    Any adverse events either observed or reported by the participant were recorded. SAEs causally related could be either possibly or probably related. A participant may have more than one SAE with outcome death, hence the total number of deaths summed from SAEs are more than the total number of deaths in the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    L1 (low dose, monthly review)
    Reporting group description
    		 Low dose, monthly review. Deaths are those occurring whilst in trial.

    Reporting group title
    S1 (standard dose, monthly review)
    Reporting group description
    		 Standard dose, monthly review. Deaths are those occurring whilst in trial.

    Reporting group title
    L2 (low dose, bi-monthly review)
    Reporting group description
    		 Low dose, bi-monthly review. Deaths are those occurring whilst in trial.

    Reporting group title
    S2 (standard dose, bi-monthly review)
    Reporting group description
    		 Standard dose, bi-monthly review. Deaths are those occurring whilst in trial.

    Serious adverse events
    		 L1 (low dose, monthly review) S1 (standard dose, monthly review) L2 (low dose, bi-monthly review) S2 (standard dose, bi-monthly review)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    57 / 204 (27.94%)
    48 / 203 (23.65%)
    49 / 203 (24.14%)
    58 / 202 (28.71%)
         number of deaths (all causes)
    11
    9
    8
    8
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified
         subjects affected / exposed
    16 / 204 (7.84%)
    13 / 203 (6.40%)
    12 / 203 (5.91%)
    15 / 202 (7.43%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 14
    0 / 12
    0 / 15
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 3
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    4 / 204 (1.96%)
    5 / 203 (2.46%)
    2 / 203 (0.99%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    3 / 204 (1.47%)
    2 / 203 (0.99%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Reproductive system and breat disorder
         subjects affected / exposed
    0 / 204 (0.00%)
    1 / 203 (0.49%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    6 / 204 (2.94%)
    8 / 203 (3.94%)
    7 / 203 (3.45%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 9
    2 / 8
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 1
    Psychiatric disorders
    Psychiatric disorder
         subjects affected / exposed
    0 / 204 (0.00%)
    1 / 203 (0.49%)
    1 / 203 (0.49%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Investigation
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    9 / 204 (4.41%)
    10 / 203 (4.93%)
    9 / 203 (4.43%)
    9 / 202 (4.46%)
         occurrences causally related to treatment / all
    1 / 14
    1 / 11
    0 / 10
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    7 / 204 (3.43%)
    7 / 203 (3.45%)
    9 / 203 (4.43%)
    6 / 202 (2.97%)
         occurrences causally related to treatment / all
    4 / 9
    4 / 11
    3 / 10
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    3 / 6
    0 / 2
    0 / 1
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    6 / 204 (2.94%)
    4 / 203 (1.97%)
    8 / 203 (3.94%)
    10 / 202 (4.95%)
         occurrences causally related to treatment / all
    3 / 6
    2 / 4
    4 / 8
    5 / 10
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    2 / 204 (0.98%)
    0 / 203 (0.00%)
    3 / 203 (1.48%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye disorders
         subjects affected / exposed
    4 / 204 (1.96%)
    2 / 203 (0.99%)
    2 / 203 (0.99%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 2
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 204 (0.98%)
    3 / 203 (1.48%)
    4 / 203 (1.97%)
    12 / 202 (5.94%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    1 / 5
    2 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    3 / 204 (1.47%)
    2 / 203 (0.99%)
    2 / 203 (0.99%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorder
         subjects affected / exposed
    3 / 204 (1.47%)
    3 / 203 (1.48%)
    3 / 203 (1.48%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine disorder
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculosketal and connective tissue disorder
         subjects affected / exposed
    1 / 204 (0.49%)
    1 / 203 (0.49%)
    0 / 203 (0.00%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    9 / 204 (4.41%)
    3 / 203 (1.48%)
    12 / 203 (5.91%)
    8 / 202 (3.96%)
         occurrences causally related to treatment / all
    0 / 11
    1 / 4
    0 / 16
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 1
    Metabolism and nutrition disorders
    Metabolism and nutrition disorder
         subjects affected / exposed
    0 / 204 (0.00%)
    1 / 203 (0.49%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4.9%
    Non-serious adverse events
    		 L1 (low dose, monthly review) S1 (standard dose, monthly review) L2 (low dose, bi-monthly review) S2 (standard dose, bi-monthly review)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    143 / 204 (70.10%)
    157 / 203 (77.34%)
    137 / 203 (67.49%)
    141 / 202 (69.80%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
         subjects affected / exposed
    4 / 204 (1.96%)
    7 / 203 (3.45%)
    1 / 203 (0.49%)
    3 / 202 (1.49%)
         occurrences all number
    4
    10
    2
    4
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    10 / 204 (4.90%)
    23 / 203 (11.33%)
    8 / 203 (3.94%)
    11 / 202 (5.45%)
         occurrences all number
    12
    25
    10
    14
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    24 / 204 (11.76%)
    36 / 203 (17.73%)
    23 / 203 (11.33%)
    32 / 202 (15.84%)
         occurrences all number
    32
    43
    25
    41
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    37 / 204 (18.14%)
    51 / 203 (25.12%)
    23 / 203 (11.33%)
    26 / 202 (12.87%)
         occurrences all number
    48
    73
    30
    27
    Immune system disorders
    Immune system disorder
         subjects affected / exposed
    1 / 204 (0.49%)
    3 / 203 (1.48%)
    2 / 203 (0.99%)
    2 / 202 (0.99%)
         occurrences all number
    1
    3
    2
    2
    Social circumstances
    Social circumstances
         subjects affected / exposed
    0 / 204 (0.00%)
    2 / 203 (0.99%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    2 / 204 (0.98%)
    4 / 203 (1.97%)
    0 / 203 (0.00%)
    3 / 202 (1.49%)
         occurrences all number
    3
    5
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    18 / 204 (8.82%)
    25 / 203 (12.32%)
    27 / 203 (13.30%)
    20 / 202 (9.90%)
         occurrences all number
    23
    40
    35
    31
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    3 / 204 (1.47%)
    8 / 203 (3.94%)
    8 / 203 (3.94%)
    3 / 202 (1.49%)
         occurrences all number
    3
    8
    10
    3
    Investigations
    Investigation
         subjects affected / exposed
    14 / 204 (6.86%)
    17 / 203 (8.37%)
    12 / 203 (5.91%)
    9 / 202 (4.46%)
         occurrences all number
    18
    18
    16
    11
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    42 / 204 (20.59%)
    49 / 203 (24.14%)
    32 / 203 (15.76%)
    33 / 202 (16.34%)
         occurrences all number
    65
    77
    44
    55
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    12 / 204 (5.88%)
    13 / 203 (6.40%)
    9 / 203 (4.43%)
    14 / 202 (6.93%)
         occurrences all number
    18
    18
    11
    16
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    31 / 204 (15.20%)
    43 / 203 (21.18%)
    32 / 203 (15.76%)
    36 / 202 (17.82%)
         occurrences all number
    46
    56
    47
    46
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    5 / 204 (2.45%)
    7 / 203 (3.45%)
    5 / 203 (2.46%)
    4 / 202 (1.98%)
         occurrences all number
    6
    8
    7
    4
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    2 / 204 (0.98%)
    10 / 203 (4.93%)
    4 / 203 (1.97%)
    2 / 202 (0.99%)
         occurrences all number
    2
    10
    4
    2
    Eye disorders
    Eye disorder
         subjects affected / exposed
    75 / 204 (36.76%)
    82 / 203 (40.39%)
    67 / 203 (33.00%)
    57 / 202 (28.22%)
         occurrences all number
    133
    158
    102
    88
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    22 / 204 (10.78%)
    29 / 203 (14.29%)
    24 / 203 (11.82%)
    16 / 202 (7.92%)
         occurrences all number
    35
    40
    32
    32
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    1 / 204 (0.49%)
    1 / 203 (0.49%)
    1 / 203 (0.49%)
    2 / 202 (0.99%)
         occurrences all number
    1
    1
    1
    2
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    11 / 204 (5.39%)
    12 / 203 (5.91%)
    13 / 203 (6.40%)
    8 / 202 (3.96%)
         occurrences all number
    11
    15
    15
    8
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    7 / 204 (3.43%)
    6 / 203 (2.96%)
    9 / 203 (4.43%)
    2 / 202 (0.99%)
         occurrences all number
    8
    6
    10
    2
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    1 / 203 (0.49%)
    2 / 202 (0.99%)
         occurrences all number
    0
    0
    1
    4
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    26 / 204 (12.75%)
    26 / 203 (12.81%)
    20 / 203 (9.85%)
    18 / 202 (8.91%)
         occurrences all number
    36
    31
    25
    20
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    52 / 204 (25.49%)
    58 / 203 (28.57%)
    48 / 203 (23.65%)
    49 / 202 (24.26%)
         occurrences all number
    85
    108
    78
    86
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    10 / 204 (4.90%)
    6 / 203 (2.96%)
    4 / 203 (1.97%)
    6 / 202 (2.97%)
         occurrences all number
    11
    8
    4
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2010
    1. Sample size calculations were not consistent across the protocol. Changes resulted in changes to inclusion/exclusion 2. Additional expected ocular and non-ocular AEs/SAEs 3. The sponsor to retain responsibility for the reporting of SUSARs to the authorities 4. Sites in Sherwood Forest and Kettering have a change in Principal Investigator 5. Northampton General Hospital, Chesterfield Royal Hospital and Leicester Royal Infirmary no longer participating in the study 6. Replacement of patient representative from the Macular Disease Society 7. Minor re-wording of the Patient Information Sheet
    06 Apr 2011
    Changes are required to the protocol to include DNA testing for patients who are randomised to the study. Observational patients are being included in the study. Changes are also required to the initial application to the REC and MHRA on confidentiality Changes to patient information sheet and consent form. Inclusion of Leicester as a site.
    29 Nov 2011
    The background section has been updated with new scientific evidence. Changes have also been made to: - comply with Sponsor’s template. - the description of eligibility and review of patients with respect to criteria of withdrawal from the trial. DNA testing for patients who are randomised to the study has been removed. Patient Information Sheet, Patient Consent Form, Patient Health Record, Patient Study Card, TANDEM Poster, Post injection sheet updated
    15 May 2012
    The protocol reflects the following changes:  Move from Bristol Coordinating Centre to Nottingham Clinical Trials Unit.  Removal of observational study Patient information sheet, patient card and poster also amended
    13 Sep 2013
    Safety section (reporting procedures) updated following MHRA inspection visit of 30th July 2013. Change of statistician Update of DMC wording to reflect role and remit within the trial.
    13 Jan 2015
    Minor wording amendments made to:  11.2.1 ‘SAE Reporting’- reporting timeframe has been clarified.  13.1 ‘Proposed actions to comply with 'The Medicines for Human Use (Clinical Trials) Regulations 2004': Update of wording to reflect Sponsor audit procedure  Addition of new references.
    25 Nov 2015
    Minor wording clarifications made to:  Protocol synopsis; study drug low dose weight amended  4.3 Participating centres; PCTs amended to CCGs  5.1.3 Unmasking Procedure now referenced Formatting applied throughout protocol Derby centre closed. The Patient Information Sheet updated to reflect the use of Eyelea® for wAMD in standard NHS practice.
    11 May 2016
    Removal of the interim analysis Changes to reflect the transfer of Serious Adverse Events and Deviation reporting from the sponsor (Nottingham University Hospitals Research and Innovation) to the Nottingham Clinical Trials Unit.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Dec 2011
    Temporary suspension due to move from Bristol to Nottingham coordinating centre, modification of baseline data collection and database. Dates are of substantial amendments. The last randomisation prior to suspension was 18-Nov-2011; the first after suspension was 30-Jul-2012.
    15 May 2012

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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