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    Clinical Trial Results:
    Management of recurrent pterygium to prevent visual impairment(REPEAT)

    Summary
    EudraCT number
    2015-003217-20
    Trial protocol
    GB  
    Global end of trial date
    11 Apr 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Apr 2019
    First version publication date
    25 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15073
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02530801
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Nottingham
    Sponsor organisation address
    Jubilee Campus, Triumph Road, Nottingham, United Kingdom, NG8 1DH
    Public contact
    Harminder Dua, University of Nottingham, 0115 9709796, harminder.dua@nottingham.ac.uk
    Scientific contact
    Harminder Dua, University of Nottingham, 0115 8467906, sponsor@nottingham.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of combined 5FU and Avastin injections in the treatment of recurrent pterygium.
    Protection of trial subjects
    Pregnant women, women aiming for conception, and nursing mothers were excluded from the study. Patients under 18 years of age were also excluded. Dose adjustment was not expected to be needed for patients with renal or hepatic impairment. There is no evidence in the literature that it affects spermatogenesis in men who are aiming to father a child. Therefore they were not excluded from the study but were informed that there is no evidence in the literature regarding whether Avastin® can affect sperm. Participants were asked to contact the study site immediately in the event of any serious adverse event. History would be taken and recorded and meticulous eye examination done for the patient. All adverse events were recorded, appropriately treated and closely monitored until resolution, stabilisation, or until it has been shown that the study medication or treatment is not the cause. The Chief Investigator (delegated responsibility by the Sponsor) would be informed immediately (within 24 hours) of any serious adverse events and would determine seriousness and causality in conjunction with any treating medical practitioners. All serious adverse events were to be recorded and reported to the MHRA and REC as part of the annual Development Safety Update Reports. SUSARs were to be reported within the statutory timeframes to the MHRA and REC as stated below.
    Background therapy
    Antibiotic eye drops (chloramphenicol)
    Evidence for comparator
    No comparator was used for this trial.
    Actual start date of recruitment
    01 Dec 2015
    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: 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)
    16
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were recruited from specialist cornea and ocular surface clinics of Professor HS Dua at Nottingham University Hospitals NHS Trust between 10.01.2017 and 09.11.2017. The trial setting is a secondary care hospital in the UK.

    Pre-assignment
    Screening details
    Patient meets all eligibility criteria as per protocol including age over the age of 18, able to give informed consent, presenting with either early or recurrent pterygium, able to tolerate injection, not pregnant or breastfeeding or planning on becoming pregnant, do not have concurrent eye conditions that would make them unsuitable.

    Period 1
    Period 1 title
    Pre-injection
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Treatment Group
    Arm description
    Patients receiving Avastin and 5 flurouracil.
    Arm type
    Experimental

    Investigational medicinal product name
    5 Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subconjunctival use
    Dosage and administration details
    0.15 ml of 5FU (3.75mg) administered into the body of the pterygium. Up to 5 injections at 5 visits could be given.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subconjunctival use
    Dosage and administration details
    0.15 ml of Avastin® (3.75mg) administered in the body of the pterygium lesion. Up to 5 injections at 5 visits could be given.

    Number of subjects in period 1
    Treatment Group
    Started
    20
    Completed
    20
    Period 2
    Period 2 title
    Post-injection series
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Treatment Group
    Arm description
    Patients receiving Avastin and 5 flurouracil.
    Arm type
    Experimental

    Investigational medicinal product name
    5 Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subconjunctival use
    Dosage and administration details
    0.15 ml of 5FU (3.75mg) administered into the body of the pterygium. Up to 5 injections at 5 visits could be given.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subconjunctival use
    Dosage and administration details
    0.15 ml of Avastin® (3.75mg) administered in the body of the pterygium lesion. Up to 5 injections at 5 visits could be given.

    Number of subjects in period 2
    Treatment Group
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pre-injection
    Reporting group description
    -

    Reporting group values
    Pre-injection Total
    Number of subjects
    20 20
    Age categorical
    All participants were aged over 18, there was no upper age limit.
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    16 16
        From 65-84 years
    4 4
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    54 (22 to 83) -
    Gender categorical
    Units: Subjects
        Female
    8 8
        Male
    12 12
    Type of pterygium
    Units: Subjects
        Primary
    16 16
        Recurrent
    4 4
    Total Number of Injections Received
    Units: Subjects
        1 injection
    0 0
        2 injections
    2 2
        3 injections
    1 1
        4 injections
    1 1
        5 injections
    16 16

    End points

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    End points reporting groups
    Reporting group title
    Treatment Group
    Reporting group description
    Patients receiving Avastin and 5 flurouracil.
    Reporting group title
    Treatment Group
    Reporting group description
    Patients receiving Avastin and 5 flurouracil.

    Primary: Arrest of progression and/or regression of thickness of the conjunctiva at the site of the lesion.

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    End point title
    Arrest of progression and/or regression of thickness of the conjunctiva at the site of the lesion.
    End point description
    The response to treatment was judged clinically by biomicroscopy examination (when no further advance of the lesion was noted over three follow-up visits, 1-2 weeks apart) and quantitatively by comparison with pre-treatment slit lamp photographs (arrest of progression and/or regression of vascularity and thickness of the conjunctiva at the site of the lesion). The degree of vascularity and thickness of the conjunctiva was assessed using a semi- automatic method by comparison of the pre and post treatment digital eye photographs by two independent blind reviewers.
    End point type
    Primary
    End point timeframe
    After a maximum of 5 injections of 5FU and Avastin over the course of six months
    End point values
    Treatment Group Treatment Group
    Number of subjects analysed
    20 [1]
    20 [2]
    Units: microns
        arithmetic mean (full range (min-max))
    323 (94 to 620)
    285 (88 to 535)
    Notes
    [1] - 20 subjects were analysed pre and post their series of injections.
    [2] - 20 subjects were analysed pre and post their series of injections.
    Statistical analysis title
    Reduction in thickness pre and post injection
    Statistical analysis description
    As this is a single arm trial the comparison groups are the 20 participants pre and post injection.
    Comparison groups
    Treatment Group v Treatment Group
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.0078
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Mean difference (final values)
    Point estimate
    35.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.7
         upper limit
    59.9
    Notes
    [3] - Comparison of pterygium thickness pre and post injection series.

    Secondary: Disappearance of redness

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    End point title
    Disappearance of redness
    End point description
    Mean reduction in clinical grade post injection.
    End point type
    Secondary
    End point timeframe
    After a maximum of five injections over a six month period.
    End point values
    Treatment Group Treatment Group
    Number of subjects analysed
    20 [4]
    20 [5]
    Units: Clinical scoring
        arithmetic mean (full range (min-max))
    2.313 (2 to 3)
    1.625 (1 to 3)
    Notes
    [4] - 20 subjects were analysed pre and post their series of injections.
    [5] - 20 subjects were analysed pre and post their series of injections.
    Statistical analysis title
    Reduction in clinical grade pre and post injection
    Comparison groups
    Treatment Group v Treatment Group
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.0004
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    0.367
         upper limit
    1.008
    Notes
    [6] - Reduction in clinical grade pre and post injection

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 2 weeks post-injection.
    Adverse event reporting additional description
    Participants will be asked to contact the study site immediately in the event of any serious adverse event. All adverse events will be recorded and closely monitored until resolution, stabilisation, or until it has been shown that the study medication or treatment is not the cause.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    All participants who received Avastin and 5 Fluorouracil.

    Serious adverse events
    Overall Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Overall Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
    Eye disorders
    Superficial punctate keratitis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jun 2016
    Primary pterygium was added to the inclusion criteria and the sample size was increased to 40. An additional co-investigator was added.
    12 Jan 2017
    A tissue collection sub-study was added to obtain consent from patients who received injections to use the pterygium tissue after being surgically excised, as surgical excision is the standard care in pterygium patients, and also from patients who have had injections as part of their normal standard of care outside the study as they may also have their residual pterygium excised. The tissue was to be examined to ascertain what effect the injections had on the pterygium. This tissue is normally sent to the laboratory for routine examination under the microscope. The tissue will be disposed of at the end of the study in accordance with the Human Tissue Act.
    26 Mar 2018
    Consent to be sought from participants that any remaining pterygium tissue samples may be stored and used in possible future research.
    09 Apr 2018
    Inclusion of the retrospective data of the patients who have already received the treatment in the protocol as part of their NHS standard care. Thirteen patients have already provided their consent, using the information sheet and consent form which talk about their prospective treatment, but it was clearly explained to them that they were consenting to the use of their retrospective data, where they have already received the trial treatment as part of their standard care.

    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.
    Although the recruitment target had been amended to 40, the decision was made to stop recruitment at 20 participants as sufficient data was collected to achieve the protocol objectives.
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