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    Clinical Trial Results:
    Avastin-Injections in Age Related Macular Degeneration: Prospective Study for Optimal Frequency and Follow-up Determination

    Summary
    EudraCT number
    		 2007-003766-17
    Trial protocol
    		 NL  
    Global end of trial date
    27 May 2013

    Results information
    Results version number
    		 v4(current)
    This version publication date
    23 Dec 2020
    First version publication date
    25 Dec 2014
    Other versions
    		 v1 (removed from public view) , v2 (removed from public view) , v3
    Version creation reason
    • New data added to full data set
    publications

    Trial information

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    Trial identification
    Sponsor protocol code
    2007-06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Nederlands Trial Register: NTR1174
    Sponsors
    Sponsor organisation name
    The Rotterdam Eye Hospital
    Sponsor organisation address
    PO Box 70030, Rotterdam, Netherlands, 3000LM
    Public contact
    Rotterdam Ophthalmic Institute, The Rotterdam Eye Hospital, +31 10 4023449, roi@oogziekenhuis.nl
    Scientific contact
    Rotterdam Ophthalmic Institute, The Rotterdam Eye Hospital, +31 10 4023449, roi@oogziekenhuis.nl
    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
    03 Jun 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 May 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the optimal Avastin injection schedule.
    Protection of trial subjects
    No specific measures.
    Background therapy
    		 Age-related macular degeneration (ARMD) results in a deterioration of the central retinal function, and is the leading cause of blindness in people over 50 years of age in Europe and the USA. The wet form of ARMD, with choroidal neovascularization, is more aggressive and may progress more rapidly to blindness. Recently, Lucentis® has been registered for treatment of wet ARMD, but is (as yet) not reimbursed by health care insurance. Avastin® appears to be a cost-effective alternative for Lucentis®, but an optimal injection schedule has not been determined so far. A reduction of the number of injections, without loss of treatment efficacy, would have a number of beneficial effects: a decrease of the risk associated with intravitreal injection (such as endophthalmitis), cost-effectiveness and reduced ophthalmic work-load.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jun 2008
    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
    Netherlands: 311
    Worldwide total number of subjects
    311
    EEA total number of subjects
    311
    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)
    0
    From 65 to 84 years
    246
    85 years and over
    65

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with exudative ARMD.

    Pre-assignment
    Screening details
    		 Use of coumarin-derivatives at the time of inclusion. Clinical significant CVA or MCI in the 6 months prior to planned inclusion.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Every 4 weeks
    Arm description
    		 Avastin injection every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    EU/1/04/300/001
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1.25 mg (in 0.05 ml) every 4 weeks.

    Arm title
    		 Every 6 weeks.
    Arm description
    		 Avastin injection every 6 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    EU/1/04/300/001
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1.25 mg (in 0.05 ml) every 6 weeks.

    Arm title
    		 Every 8 weeks.
    Arm description
    		 Avastin injection every 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    EU/1/04/300/001
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1.25 mg (in 0.05 ml) every 8 weeks.

    Arm title
    		 Visit every 4 weeks.
    Arm description
    		 Visit every 4 weeks, Avastin injection on demand.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    EU/1/04/300/001
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1.25 mg (in 0.05 ml) on demand.

    Arm title
    		 Visit every 8 weeks.
    Arm description
    		 Visit every 8 weeks, Avastin injection on demand.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    EU/1/04/300/001
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1.25 mg (in 0.05 ml) on demand.

    Number of subjects in period 1
    		Every 4 weeks Every 6 weeks. Every 8 weeks. Visit every 4 weeks. Visit every 8 weeks.
    Started
    64
    63
    64
    60
    60
    Completed
    46
    57
    54
    51
    57
    Not completed
    18
    6
    10
    9
    3
         Lost to follow-up
    18
    6
    10
    9
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Every 4 weeks
    Reporting group description
    		 Avastin injection every 4 weeks.

    Reporting group title
    Every 6 weeks.
    Reporting group description
    		 Avastin injection every 6 weeks

    Reporting group title
    Every 8 weeks.
    Reporting group description
    		 Avastin injection every 8 weeks.

    Reporting group title
    Visit every 4 weeks.
    Reporting group description
    		 Visit every 4 weeks, Avastin injection on demand.

    Reporting group title
    Visit every 8 weeks.
    Reporting group description
    		 Visit every 8 weeks, Avastin injection on demand.

    Reporting group values
    		 Every 4 weeks Every 6 weeks. Every 8 weeks. Visit every 4 weeks. Visit every 8 weeks. Total
    Number of subjects
    		 64 63 64 60 60 311
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 77.7 ( 6.8 ) 78.6 ( 6.5 ) 79.4 ( 6.2 ) 77.6 ( 6.8 ) 79.1 ( 7.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 46 38 43 36 38 201
        Male
    		 18 25 21 24 22 110

    End points

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    End points reporting groups
    Reporting group title
    Every 4 weeks
    Reporting group description
    		 Avastin injection every 4 weeks.

    Reporting group title
    Every 6 weeks.
    Reporting group description
    		 Avastin injection every 6 weeks

    Reporting group title
    Every 8 weeks.
    Reporting group description
    		 Avastin injection every 8 weeks.

    Reporting group title
    Visit every 4 weeks.
    Reporting group description
    		 Visit every 4 weeks, Avastin injection on demand.

    Reporting group title
    Visit every 8 weeks.
    Reporting group description
    		 Visit every 8 weeks, Avastin injection on demand.

    Primary: Visual acuity.

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    End point title
    		 Visual acuity.
    End point description
    End point type
    Primary
    End point timeframe
    At 1 year.
    End point values
    		 Every 4 weeks Every 6 weeks. Every 8 weeks. Visit every 4 weeks. Visit every 8 weeks.
    Number of subjects analysed
    46
    57
    54
    51
    57
    Units: Letters gained (ETDRS chart).
        arithmetic mean (standard deviation)
    1.9 ( 13.8 )
    1.6 ( 11 )
    6 ( 8.9 )
    5.6 ( 10.2 )
    4.6 ( 12 )
    Statistical analysis title
    		 VA gain.
    Comparison groups
    Every 4 weeks v Every 6 weeks. v Every 8 weeks. v Visit every 4 weeks. v Visit every 8 weeks.
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    One year follow up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Every 4 weeks.
    Reporting group description
    		 -

    Reporting group title
    Every 6 weeks.
    Reporting group description
    		 -

    Reporting group title
    Every 8 weeks.
    Reporting group description
    		 -

    Reporting group title
    Visit every 4 weeks, injection on demand.
    Reporting group description
    		 -

    Reporting group title
    Visit every 8 weeks, injection on demand.
    Reporting group description
    		 -

    Serious adverse events
    		 Every 4 weeks. Every 6 weeks. Every 8 weeks. Visit every 4 weeks, injection on demand. Visit every 8 weeks, injection on demand.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 64 (14.06%)
    4 / 63 (6.35%)
    9 / 64 (14.06%)
    3 / 60 (5.00%)
    2 / 60 (3.33%)
         number of deaths (all causes)
    2
    1
    0
    3
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
    1 / 64 (1.56%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 63 (0.00%)
    2 / 64 (3.13%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    3 / 60 (5.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    Blood and lymphatic system disorders
    Atherothrombotic event.
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 63 (1.59%)
    1 / 64 (1.56%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal pigment epithelial tear
         subjects affected / exposed
    2 / 64 (3.13%)
    2 / 63 (3.17%)
    4 / 64 (6.25%)
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis or pseudoendophthalmitis
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Other ocular event.
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Every 4 weeks. Every 6 weeks. Every 8 weeks. Visit every 4 weeks, injection on demand. Visit every 8 weeks, injection on demand.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    Eye disorders
    Vitreous hemorrhage
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/23773796
    http://www.ncbi.nlm.nih.gov/pubmed/30369062
    http://www.ncbi.nlm.nih.gov/pubmed/32666333
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