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    Clinical Trial Results:
    A combined Phase IIa / IIb study of the efficacy, safety, and tolerability of repeated topical doses of regorafenib eye drops, in treatment-naive subjects with neovascular age related macular degeneration

    Summary
    EudraCT number
    		 2012-003763-22
    Trial protocol
    		 HU   DE   CZ   SK  
    Global end of trial date
    17 Jun 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    04 Sep 2016
    First version publication date
    28 Jun 2016
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Bayer sponsor contact information to be updated

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY73-4506/15984
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02222207
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    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
    17 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectve for part A is to assess the effect of treatment with regorafenib eye drops on visual acuity at Study Week 4 and at Study Week 12 in subjects with subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Oct 2014
    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
    Czech Republic: 13
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Israel: 8
    Worldwide total number of subjects
    52
    EEA total number of subjects
    44
    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)
    7
    From 65 to 84 years
    38
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 27 centers, between 10 October 2014 (first subject first visit) and 17 June 2015 (last subject last visit).

    Pre-assignment
    Screening details
    		 Study was planned to be conducted in 2 parts, Part A and B, in Part A 89 subjects were enrolled, of them 37 were screen failure and 52 were assigned to treatment, 1 subject was excluded from all analysis sets due to protocol deviations and 51 subjects were analyzed. Part B was not initiated and the study terminated following completion of Part A.

    Period 1
    Period 1 title
    Overall Trial
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part A Regorafenib
    Arm description
    		 Subjects self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL), 1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    BAY73-4506
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ocular use
    Dosage and administration details
    Self-administration of 30 mg/mL, 25 mcL, 1 drop of Regorafenib eye drops, TID to the study eye for 12 weeks.

    Number of subjects in period 1
    		Part A Regorafenib
    Started
    52
    Treated and valid for Full Analysis Set
    51
    Completed
    48
    Not completed
    4
         Death
    1
         Other
    2
         Adverse event
    1
    Period 2
    Period 2 title
    Baseline period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part A Regorafenib
    Arm description
    		 Subjects self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL),1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    BAY73-4506
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ocular use
    Dosage and administration details
    Self-administration of 30 mg/mL, 25 mcL, 1 drop of Regorafenib eye drops, topically TID to the study eye for 12 weeks.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline data is available only for treated participants and not randomized participants, hence this period has been created to report the baseline data.
    Number of subjects in period 2
    		Part A Regorafenib
    Started
    51
    Completed
    51

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Part A Regorafenib
    Reporting group description
    		 Subjects self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL),1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all the enrolled subjects were treated with study drugs. As baseline only included treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.
    Reporting group values
    		 Part A Regorafenib Total
    Number of subjects
    		 51
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 75 ± 8.4 -
    Gender categorical
    Units: Subjects
        Female
    		 29 29
        Male
    		 22 22

    End points

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    End points reporting groups
    Reporting group title
    Part A Regorafenib
    Reporting group description
    		 Subjects self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL), 1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.
    Reporting group title
    Part A Regorafenib
    Reporting group description
    		 Subjects self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL),1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.

    Subject analysis set title
    Full Analysis Set (FAS-Part A)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS (N=51) included subjects who received at least one dose of study medication.

    Subject analysis set title
    Safety analysis set (SAF-Part A)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N=51) included subjects who received at least one dose of study medication.

    Primary: Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Study Week 4 for Study Part A

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    End point title
    		 Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Study Week 4 for Study Part A [1]
    End point description
    Subjects will be assessed at each clinic visit for best corrected visual acuity using the early treatment diabetic retinopathy study chart. Visual function of the study eye and the fellow eye was assessed using the ETDRS. The subject’s ETDRS testing score was recorded in the appropriate eCRF page at each study visit. For patients that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    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: Statistical analysis were provided as an attachment
    End point values
    		 Part A Regorafenib
    Number of subjects analysed
    50 [2]
    Units: Score on scale
        arithmetic mean (standard deviation)
    1.18 ± 7.55
    Attachments
    		 Untitled (Filename: 15984_Statistical analysis of change in BCVA in ETDRS letter score from baseline at Study Week 4.pdf)
    Notes
    [2] - FAS
    No statistical analyses for this end point

    Primary: Change From Baseline in BCVA as Measured by ETDRS Letter Score at Study Week 12 for Study Part A

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    End point title
    		 Change From Baseline in BCVA as Measured by ETDRS Letter Score at Study Week 12 for Study Part A [3]
    End point description
    Subjects were assessed at each clinic visit for best corrected visual acuity using the early treatment diabetic retinopathy study chart. Visual function of the study eye and the fellow eye was assessed using the ETDRS protocol. ETDRS testing score was recorded in the appropriate eCRF page at each study visit. For patients that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    Notes
    [3] - 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: Statistical analysis were provided as an attachment
    End point values
    		 Part A Regorafenib
    Number of subjects analysed
    50 [4]
    Units: Score on scale
        arithmetic mean (standard deviation)
    -2.36 ± 7.68
    Attachments
    		 Untitled (Filename: 15984_Statistical analysis of change in BCVA in ETDRS letter score at Study Week 12.pdf)
    Notes
    [4] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Individual Changes in BCVA of greater than equal to (>=) 0 Letters of Vision From Study Week 4 to Week 12 for Study Part A

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    End point title
    		 Percentage of Subjects With Individual Changes in BCVA of greater than equal to (>=) 0 Letters of Vision From Study Week 4 to Week 12 for Study Part A
    End point description
    Subjects were assessed at each clinic visit for BCVA using the early treatment diabetic retinopathy study chart. For patients that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 12
    End point values
    		 Part A Regorafenib
    Number of subjects analysed
    50 [5]
    Units: percentage of subjects
        number (not applicable)
    42
    Notes
    [5] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With a Loss in BCVA of >= 10 Letters From Baseline to Study Week 12 for Study Part A

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    End point title
    		 Percentage of Subjects With a Loss in BCVA of >= 10 Letters From Baseline to Study Week 12 for Study Part A
    End point description
    Subjects were assessed at each clinic visit for BCVA using the early treatment diabetic retinopathy study chart. For patients that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Part A Regorafenib
    Number of subjects analysed
    50 [6]
    Units: percentage of subjects
        number (not applicable)
    16
    Notes
    [6] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study treatment until 30 days after last dose of study drug treatment (up to Week 16)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Part A Regorafenib
    Reporting group description
    		 Subjects self-administered 30 mg/mL, 25 mcL, 1 drop of regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.

    Serious adverse events
    		 Part A Regorafenib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 51 (5.88%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Investigations
    Visual acuity tests abnormal
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A Regorafenib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 51 (21.57%)
    Investigations
    Visual acuity tests abnormal
         subjects affected / exposed
    5 / 51 (9.80%)
         occurrences all number
    6
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    6 / 51 (11.76%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Feb 2015
    Addition of subfoveal fibrosis in exclusion criteria; Clarification of the exclusion of subjects requiring steroid treatment; Deletion of controlled glaucoma as an exclusion criteria; Inclusion of a description of how ranibizumab will be used.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Jun 2015
    The study was prematurely terminated since pre-defined proof of concept (PoC) criteria were not met in Part A, hence part B was not intiated.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    As the study was prematurely terminated since pre-defined proof of concept (PoC) criteria were not met in Part A, hence part B was not initiated. Part B related end points and data were not reported since it is not conducted.
    For support, Contact us.
    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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