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    Clinical Trial Results:
    Intravitreal versus submacular injection of rtPA for acute submacular haemorrhages.

    Summary
    EudraCT number
    		 2010-023636-17
    Trial protocol
    		 NL  
    Global end of trial date
    19 Mar 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Mar 2016
    First version publication date
    18 Mar 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of online reference.

    Trial information

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    Trial identification
    Sponsor protocol code
    OZR-2010-22
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Nederlands Trial Register: NTR3359
    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
    30 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To examine which route of rtPA administration (submacular or intravitreal) is most effective with respect to dislocation and/or volume reduction of SMH at 3 months.
    Protection of trial subjects
    None specified.
    Background therapy
    		 Submacular haemorrhage (SMH) is a severe complication of age-related macular degeneration (AMD). If untreated, the SMH itself will cause irreversible damage to the retina and retinal pigment epithelium (RPE). Recombinant tissue plasminogen activator (rtPA) is a fibrolytic enzyme which can liquefy blood clots by converting plasminogen into active plasmin, which is needed for the breakdown of fibrin.Two treatment modalities of SMH have been compared.
    Evidence for comparator
    		 In this study, the investigational topic was the route of administration of rtPA: submacular (Arm 1) and intravitreal (Arm 2).
    Actual start date of recruitment
    13 Sep 2013
    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: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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
    19
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 Consecutive patients with SMH existing ≤ 14 days at time of surgery.

    Pre-assignment
    Screening details
    		 INR.

    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
    		 Submacular rtPA
    Arm description
    		 Submacular injection of rtPA with pars plana vitrectomy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    alteplase
    Investigational medicinal product code
    RVG 103374
    Other name
    Actilyse Cathflo®
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Submacular injection: 0.1 ml; 25 µg rtPA.

    Arm title
    		 Intravitreal rtPA.
    Arm description
    		 Intravitreal injection of rtPA.
    Arm type
    		 Experimental

    Investigational medicinal product name
    alteplase
    Investigational medicinal product code
    RVG 103374
    Other name
    Actilyse Cathflo®
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Intravitreal injection: 0.1 ml; 25 µg rtPA.

    Number of subjects in period 1
    		Submacular rtPA Intravitreal rtPA.
    Started
    13
    12
    Completed
    11
    11
    Not completed
    2
    1
         Adverse event, non-fatal
    1
    1
         retinal macroaneurysms
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Submacular rtPA
    Reporting group description
    		 Submacular injection of rtPA with pars plana vitrectomy.

    Reporting group title
    Intravitreal rtPA.
    Reporting group description
    		 Intravitreal injection of rtPA.

    Reporting group values
    		 Submacular rtPA Intravitreal rtPA. Total
    Number of subjects
    		 13 12 25
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 10 9 19
        85 years and over
    		 3 3 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 79.1 ± 8.6 81.8 ± 5.1 -
    Gender categorical
    Units: Subjects
        Female
    		 7 8 15
        Male
    		 6 4 10

    End points

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    End points reporting groups
    Reporting group title
    Submacular rtPA
    Reporting group description
    		 Submacular injection of rtPA with pars plana vitrectomy.

    Reporting group title
    Intravitreal rtPA.
    Reporting group description
    		 Intravitreal injection of rtPA.

    Primary: Volume reduction.

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    End point title
    		 Volume reduction. [1]
    End point description
    End point type
    Primary
    End point timeframe
    SMH volume reduction at 6 weeks.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was intended as a pilot study and, therefore, is not adequately powered for statistical comparison.
    End point values
    		 Submacular rtPA Intravitreal rtPA.
    Number of subjects analysed
    11
    11
    Units: Proportion
        arithmetic mean (standard deviation)
    0.92 ± 0.13
    0.91 ± 0.13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Until 12 months after rtPA injection.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Submacular rtPA.
    Reporting group description
    		 -

    Reporting group title
    Intravitreal rtPA.
    Reporting group description
    		 -

    Serious adverse events
    		 Submacular rtPA. Intravitreal rtPA.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 12 (8.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Arrhythmia
    Additional description: Patient had history of arrhythmia; on this occasion hospitalized.
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
    Additional description: Patient had history of syncope; on this occasion hospitalized.
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
    Additional description: Patient was hospitalized.
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Submacular rtPA. Intravitreal rtPA.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 13 (46.15%)
    4 / 12 (33.33%)
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Retinal vascular occlusion
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Retinal pigment epithelial tear
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Macular hole
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Cataract
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Subretinal haematoma
    Additional description: Recurrent.
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    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? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Submacular injection of rtPA was performed in combination with pars plana vitrectomy and was, therefore, a more invasive procedure than intravitreal injection of rtPA. It may involve a higher risk of complications.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26807631
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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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