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    Clinical Trial Results:
    Anti-VEGF (bevacizumab/ranibizumab) versus RPE-choroid graft in the treatment of 1) non-responders to 3 intravitreal anti-VEGF injections, or 2) patients with AMD and pigment epithelium rip, or 3) patients with AMD and massive haemorrhage. A randomized trial.

    Summary
    EudraCT number
    		 2008-008259-41
    Trial protocol
    		 NL  
    Global end of trial date
    26 Aug 2011

    Results information
    Results version number
    		 v1
    This version publication date
    01 Feb 2016
    First version publication date
    11 Feb 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    OZR-2008-20
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Nederlands Trial Register: NTR1768
    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
    10 Feb 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Aug 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Aug 2011
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare visual outcome (distance and reading) and foveal fixation (biomicroscopy, microperimetry) of RPE-choroid graft translocation versus intravitreal anti-VEGF therapy at 12 and 24 months.
    Protection of trial subjects
    No specific measures.
    Background therapy
    		 Standard treatment for patients with exudative age-related macular degeneration (AMD) is intravitreal injection of anti-VEGF. Because alternatives are not available, at present, also those patients for whom this therapy probably does not help to improve prospects are initially treated with anti-VEGF. Recently, however, it has been shown that a retinal pigment epithelium (RPE)-choroid graft translocation in the treatment of patients with choroidal neovascular lesions of AMD can stabilize or even improve visual acuity. In this study, it will be investigated whether RPE-choroid graft translocation provides a better alternative to anti-VEGF medication for AMD patients for whom prospects are rather poor otherwise.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Oct 2009
    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: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    1
    From 65 to 84 years
    10
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with exudative subfoveal AMD in combination with either of the following conditions: 1) visual loss of 15 letters on the ETDRS chart after 3 anti-VEGF injections, 2) subfoveal RPE-tear, 3) massive submacular haemorrhage.

    Pre-assignment
    Screening details
    		 All patients from subgroup 3 will have their submacular haemorrhage surgically removed irrespective of the study arm they are assigned to.

    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
    		 Graft translocation.
    Arm description
    		 Retinal pigment epithelium - choroid translocation (from periphery to macular region).
    Arm type
    		 Experimental

    Investigational medicinal product name
    No product (intervention is surgical procedure).
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Living tissue equivalent
    Routes of administration
    Other use
    Dosage and administration details
    None (intervention is surgical procedure).

    Arm title
    		 Anti-VEGF.
    Arm description
    		 Continued intravitreal anti-VEGF injections.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab.
    Investigational medicinal product code
    EU/1/04/300/001
    Other name
    Avastin.
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravitreal use
    Dosage and administration details
    1.25 mg bevacizumab (0.05 ml) injections based on PrONTO protocol (Am J Ophthalmol, 2007; 143:566).

    Number of subjects in period 1
    		Graft translocation. Anti-VEGF.
    Started
    10
    10
    Completed
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Graft translocation.
    Reporting group description
    		 Retinal pigment epithelium - choroid translocation (from periphery to macular region).

    Reporting group title
    Anti-VEGF.
    Reporting group description
    		 Continued intravitreal anti-VEGF injections.

    Reporting group values
    		 Graft translocation. Anti-VEGF. Total
    Number of subjects
    		 10 10 20
    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)
    		 78.6 ( 10.4 ) 83.8 ( 8.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 5 13
        Male
    		 2 5 7

    End points

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    End points reporting groups
    Reporting group title
    Graft translocation.
    Reporting group description
    		 Retinal pigment epithelium - choroid translocation (from periphery to macular region).

    Reporting group title
    Anti-VEGF.
    Reporting group description
    		 Continued intravitreal anti-VEGF injections.

    Primary: Visual acuity

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    End point title
    		 Visual acuity
    End point description
    End point type
    Primary
    End point timeframe
    12 months post-op (LOCF).
    End point values
    		 Graft translocation. Anti-VEGF.
    Number of subjects analysed
    10
    10
    Units: LogMAR
        arithmetic mean (standard deviation)
    0.4 ( 0.7 )
    0.2 ( 0.4 )
    Statistical analysis title
    		 Visual acuity change.
    Comparison groups
    Graft translocation. v Anti-VEGF.
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months post-op.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Graft translocation.
    Reporting group description
    		 Retinal pigment epithelium - choroid translocation (from periphery to macular region).

    Reporting group title
    Anti-VEGF.
    Reporting group description
    		 Continued intravitreal anti-VEGF injections.

    Serious adverse events
    		 Graft translocation. Anti-VEGF.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 10 (30.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Graft translocation. Anti-VEGF.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
    1 / 10 (10.00%)
    Eye disorders
    Proliferative vitreoretinopathy
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    1
    Submacular hemorrhage (recurrent)
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    Hypotension (ocular)
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0

    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? Yes
    Date
    Interruption
    Restart date
    26 Aug 2011
    The multicenter study was stopped because inclusion failed in other centers. The included patient group is far too small to draw conclusions whether an RPE-choroid graft or anti-VEGF treatment is more successful. Also, this surgical group suffered an unprecedented run of complications. Both gain and loss of VA may be experienced by patients undergoing either treatment method; more gain might be possible for patients with a graft, however, in the absence of complications.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    See, van Zeeburg EJT, Thesis 2014: Chapt. 4.1. http://repub.eur.nl/pub/50334/140115_Zeeburg-Elsbeth-Janneke-Theodora-van_Part1.pdf
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    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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