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    Clinical Trial Results:
    Re-treatment with intravitreal application of ranibizumab guided by morphological macular changes documented by optical coherence tomography (OCT) in patients with macular edema due to branch retinal vein occlusion

    Summary
    EudraCT number
    		 2012-005439-10
    Trial protocol
    		 DE  
    Global end of trial date
    17 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2020
    First version publication date
    03 Jan 2020
    Other versions
    Summary report(s)
    		 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    RabOCT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01968239
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Leipzig
    Sponsor organisation address
    Ritterstr. 26, Leipzig, Germany, 04109
    Public contact
    Coordinating Investigator, Department of Ophthalmology, Universtity of Leipzig, 0049 034197 21 650, augen@medizin.uni-leipzig.de
    Scientific contact
    Coordinating Investigator, Department of Ophthalmology, Universtity of Leipzig, 0049 034197 21 650, augen@medizin.uni-leipzig.de
    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
    07 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This 2-armed randomized phase 2b (proof of concept) trial is primarily designed to provide first evidence on whether or not early reinjections of ranibizumab (when 1st morphologic macular changes were detected by OCT but not accompanied by BCVA loss - in contrast to current guidelines) will ensure better mid-term visual acuity in BRVO patients after 12 months of observation and treatment according to arm-specific retreatment criteria. Primary objective is the efficacy endpoint which is the change of best corrected visual acuity (BCVA) measured in ETDRS letters.
    Protection of trial subjects
    During the course of the trial, every patient was monitored closely concerning the described safety parameters. Besides the documentation of adverse events, this encompasses the following parameters at every visit: • Increasing of IOP (intraocular pressure) • Presence of rubeosis iridis or neovascularization in iridocorneal angle • Presence of neovascularization of optic disk (NVDs) or retinal neovascularizations elsewhere (NVEs)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2013
    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
    Germany: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    6
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between October 2013 and May 2015, 27 patients were screened and 18 patients were enrolled to the RabOCT study in one Trial site in Germany.

    Pre-assignment
    Screening details
    		 The study was composed of a pre-treatment observation period and a screening phase of 1 to 7 days. Patients wer enrolled to the study, if eligibility was confirmed.

    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
    		 OCT group
    Arm description
    		 OCT group (OCT guided re-treatment): Patients randomized to this group received the intravitreal injection of 0.5 mg ranibizumab if the morphological macular changes for recurrence of macular edema (microcystic changes with or without increase of central retinal thickness) was detected by OCT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.5 mg Ranibizumab was administered if following criteria were met: • if morphological macular changes indicating recurrence of macular edema, meaning that microcystic changes with or without increase of central retinal thickness) In total, maximal 11 injections of Ranibizumab were applied in every study patient in the treatement period of 12 months.

    Arm title
    		 Control group
    Arm description
    		 During the entire treatement phase, the re-application of intravitreal injections (0.5 mg Ranibizumab) was administered if following criteria were met: •if re-treatment criteria according to SmPC were fulfilled, i.e. any increase of CRT and concomitant decrease of BCVA In total, maximal 11 injections of Ranibizumab were applied in every study patient in the treatement period of 12 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.5 mg Ranibizumab was administered if following criteria were met: • if re-treatment criteria according to SmPC are fulfilled, i.e. any increase of CRT and concomitant decrease of BCVA In total, maximal 11 injections of Ranibizumab can be applied in every study patient in the treatement period of 12 months.

    Number of subjects in period 1
    		OCT group Control group
    Started
    9
    9
    Completed
    9
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OCT group
    Reporting group description
    		 OCT group (OCT guided re-treatment): Patients randomized to this group received the intravitreal injection of 0.5 mg ranibizumab if the morphological macular changes for recurrence of macular edema (microcystic changes with or without increase of central retinal thickness) was detected by OCT.

    Reporting group title
    Control group
    Reporting group description
    		 During the entire treatement phase, the re-application of intravitreal injections (0.5 mg Ranibizumab) was administered if following criteria were met: •if re-treatment criteria according to SmPC were fulfilled, i.e. any increase of CRT and concomitant decrease of BCVA In total, maximal 11 injections of Ranibizumab were applied in every study patient in the treatement period of 12 months.

    Reporting group values
    		 OCT group Control group Total
    Number of subjects
    		 9 9 18
    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)
    		 3 3 6
        From 65-84 years
    		 6 6 12
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.6 ( 6.8 ) 69.1 ( 8.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 5 12
        Male
    		 2 4 6
    neovascularization
    neovasculatization from ophthalmoscopy/biomicroscopy
    Units: Subjects
        No
    		 9 9 18
        Yes
    		 0 0 0
    microcysts
    microcysts present from OCT
    Units: Subjects
        No
    		 0 1 1
        Yes
    		 9 8 17
    Study eye
    Study eye
    Units: Subjects
        right
    		 4 6 10
        left
    		 5 3 8
    Body-Max-Index
    Body-Max-Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 28.5 ( 5.3 ) 30.0 ( 5.4 ) -
    BCVA of study eye
    BCVA of study eye
    Units: Letters
        arithmetic mean (standard deviation)
    		 75.7 ( 5.9 ) 72.9 ( 11.4 ) -
    CRT of study eye
    CRT of study eye
    Units: µm
        arithmetic mean (standard deviation)
    		 283.3 ( 79.0 ) 310.8 ( 162.6 ) -
    intra ocular pressure of study eye
    intra ocular pressure of study eye
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 15.2 ( 2.0 ) 15.9 ( 2.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    OCT group
    Reporting group description
    		 OCT group (OCT guided re-treatment): Patients randomized to this group received the intravitreal injection of 0.5 mg ranibizumab if the morphological macular changes for recurrence of macular edema (microcystic changes with or without increase of central retinal thickness) was detected by OCT.

    Reporting group title
    Control group
    Reporting group description
    		 During the entire treatement phase, the re-application of intravitreal injections (0.5 mg Ranibizumab) was administered if following criteria were met: •if re-treatment criteria according to SmPC were fulfilled, i.e. any increase of CRT and concomitant decrease of BCVA In total, maximal 11 injections of Ranibizumab were applied in every study patient in the treatement period of 12 months.

    Primary: Change of BCVA

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    End point title
    		 Change of BCVA
    End point description
    Based on the BCVA assessment of the study eye - performed at all study visits and measured in ETDRS letters - the primary end point was the change score in BCVA from randomization (week 1) to week 52, i.e. end of study (EoS)
    End point type
    Primary
    End point timeframe
    from randomization (week 1) to week 52, i.e. end of study (EoS)
    End point values
    		 OCT group Control group
    Number of subjects analysed
    9
    9
    Units: letters
        arithmetic mean (standard deviation)
    4.3 ( 6.1 )
    6.8 ( 10.6 )
    Statistical analysis title
    		 Estimation of the between-groups mean
    Statistical analysis description
    Estimation of the between-groups mean difference with the corresponding 95% confidence interval
    Comparison groups
    Control group v OCT group
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.349 [2]
    Method
    		 repeated-measures ANCOVA of BCVA change
    Parameter type
    		 mean difference in change
    Point estimate
    -2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.06
         upper limit
    		 6.17
    Notes
    [1] - Data description/ estimation of group difference with confidence interval
    [2] - expoloratory due to small sample size

    Secondary: Change in CRT

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    End point title
    		 Change in CRT
    End point description
    Change score in central retinal thickness (CRT), assessed by OCT between Week 1 and week 52 (EoS)
    End point type
    Secondary
    End point timeframe
    Between Week 1 and week 52 (EoS)
    End point values
    		 OCT group Control group
    Number of subjects analysed
    9
    9
    Units: µm
        arithmetic mean (standard deviation)
    -42.4 ( 76.9 )
    -80.8 ( 164.4 )
    Statistical analysis title
    		 Estimation of the between-groups mean
    Statistical analysis description
    Estimation of the between-groups mean difference with the corresponding 95% confidence interval for the secondary endpoint
    Comparison groups
    OCT group v Control group
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.23 [4]
    Method
    		 repeated-measures ANCOVA of CRT change
    Parameter type
    		 mean difference in change
    Point estimate
    38.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -94.35
         upper limit
    		 171.01
    Notes
    [3] - data description/ estimation of group difference with confidence interval
    [4] - expoloratory due to small sample size

    Secondary: Number of indicated Ranibizumab injections

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    End point title
    		 Number of indicated Ranibizumab injections
    End point description
    The number of indicated Ranibizumab injections in the two groups until last FU visit was compared by Mann-Whitney-U-Test
    End point type
    Secondary
    End point timeframe
    52 week
    End point values
    		 OCT group Control group
    Number of subjects analysed
    9
    9
    Units: Number of injections
        median (inter-quartile range (Q1-Q3))
    9 (7 to 12.5)
    8 (4.5 to 9)
    Statistical analysis title
    		 Number of indicated Ranibizumab injections
    Statistical analysis description
    The number of indicated Ranibizumab injections in the two groups until last FU visit was compared by Mann-Whitney-U-Test
    Comparison groups
    Control group v OCT group
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.258 [6]
    Method
    		 Mann-Whitney U test
    Parameter type
    		 Median difference and Hodges-Lehman st.
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 5
    Notes
    [5] - data description/ estimation of group difference with confidence interval
    [6] - expoloratory due to small sample size

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs were documented from randomization up to 30 days after the last study intervention or the termination visit, whichever was later.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    OCT group
    Reporting group description
    		 -

    Reporting group title
    Control group
    Reporting group description
    		 -

    Serious adverse events
    		 OCT group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Biopsy bladder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (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: 0%
    Non-serious adverse events
    		 OCT group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 9 (33.33%)
    3 / 9 (33.33%)
    Investigations
    Intraocular pressure increased
    Additional description: possibly injection procedure-related AE
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Injection site pain
    Additional description: possibly injection procedure-related AE
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Eye disorders
    Vitreous detachment
    Additional description: possibly injection procedure-related AE
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Eye pain
    Additional description: possibly injection procedure-related AE
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Conjunctival haemorrhage
    Additional description: possibly injection procedure-related AE
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 9 (22.22%)
         occurrences all number
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
    Additional description: possibly injection procedure-related AE
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2013
    Change of Coordinating Investigator and Authorised Representative of the Sponsor. PD Dr. habil. Matus Rehak left the Department of Ophthalmology of the University of Leipzig on January 2014. Therefore Prof. Dr. med. Peter Wiedemann took over the responsibilities of the coordinating investigator as well as of the authorised representative of the sponsor. Furthermore, some corrections and clarifications were described.
    03 Dec 2015
    Change in number of recruited patients and prolongation of trial duration and stop of recruitment phase. The recruitment of patients was low and although the recruitment phase was prolonged, 18 instead of 24 patients were allocated to the study up to May 2015. Therefore, it was decided to stop the recruitment of further patients. All patients enrolled up to this time point completed the trial according to the protocol. The statistical analyses were performed with these 18 patients.

    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
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