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    Clinical Trial Results:
    A phase II, open label, non-randomised, single centre, clinical trial of ANX776 in Healthy Volunteers and patients with Glaucoma, Age-Related Macular Degeneration, and Optic Neuritis and Down’s Syndrome

    Summary
    EudraCT number
    		 2016-002531-15
    Trial protocol
    		 GB  
    Global end of trial date
    07 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Aug 2019
    First version publication date
    22 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15/0959
    Additional study identifiers
    ISRCTN number
    		 ISRCTN10751859
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Comprehensive Clinical Trials Unit at UCL
    Sponsor organisation address
    Institute of Clinical Trials and Methodology, 90 High Holborn, London, United Kingdom, WC1V 6LJ
    Public contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.ac.uk
    Scientific contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.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
    02 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary outcome is the efficacy of the intervention ascertained by the DARC Count, which is the number of apoptosing retinal cells visualised 4 hours after the ANX776 injection in patients with Glaucoma, Age-related Macular Degeneration (AMD), Optic Neuritis (ON), Down's syndrome and in Healthy volunteers.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol, UCL CCTU Standard Operating Procedures, the Declaration of Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the Human Tissue (Quality and Safety for Human Application) Regulations 2007, the UK Data Protection Act, and the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). The following protocol pre-defined reasons for stopping the trial early for a participant were in place: unacceptable toxicity or adverse event; inter-current illness that prevents further treatment; any change in the participant’s condition that in the clinician’s opinion justifies the discontinuation of the trial. Participants were under no obligation to enter the trial and they could withdraw consent or assent / withdrawal of consent by the legal representative for Down’s syndrome participants at any time during the trial, without having to give a reason, and without their clinical care being affected.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Feb 2017
    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
    United Kingdom: 113
    Worldwide total number of subjects
    113
    EEA total number of subjects
    113
    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)
    78
    From 65 to 84 years
    31
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants for the glaucoma, AMD, optic neuritis and healthy volunteer groups were recruited through designated participant identification centres and REC approved advertisements. Participants in the Down’s syndrome arm were recruited from two pre-existing cohorts in the Cambridge Intellectual and Developmental Disabilities Research Group.

    Pre-assignment
    Screening details
    		 Eligibility criteria for all groups were those aged 18 years or above, with clear optical media in the studied eye, refractive error not higher than spherical equivalent of 10 D and women of childbearing potential identified as not pregnant. Each subgroup was enrolled into the study in accordance with group-specific inclusion/ exclusion criteria.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Glaucoma
    Arm description
    		 Subjects with at least one eye with a diagnosis of Glaucoma.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ANX776
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.4mg

    Arm title
    		 Age-related Macular Degeneration
    Arm description
    		 Subjects with Age-related Macular Degeneration (AMD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ANX776
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.4mg

    Arm title
    		 Optic Neuritis
    Arm description
    		 Subjects with clinical diagnosis of Optic neuritis (ON) affecting one eye within two years. All results including baseline data are based on the 14 eligible patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ANX776
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.4mg

    Arm title
    		 Down's Syndrome
    Arm description
    		 Subjects with confirmation of Down's Syndrome.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ANX776
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.4mg

    Arm title
    		 Healthy Volunteers
    Arm description
    		 Subjects with no evidence of any eye disease. All results including baseline data are based on the 39 eligible patients.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ANX776
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.4mg

    Number of subjects in period 1
    		Glaucoma Age-related Macular Degeneration Optic Neuritis Down's Syndrome Healthy Volunteers
    Started
    20
    19
    18
    16
    40
    Completed
    20
    19
    14
    15
    39
    Not completed
    0
    0
    4
    1
    1
         Ineligible
    -
    -
    4
    -
    1
         Missing baseline spot count
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Glaucoma
    Reporting group description
    		 Subjects with at least one eye with a diagnosis of Glaucoma.

    Reporting group title
    Age-related Macular Degeneration
    Reporting group description
    		 Subjects with Age-related Macular Degeneration (AMD).

    Reporting group title
    Optic Neuritis
    Reporting group description
    		 Subjects with clinical diagnosis of Optic neuritis (ON) affecting one eye within two years. All results including baseline data are based on the 14 eligible patients.

    Reporting group title
    Down's Syndrome
    Reporting group description
    		 Subjects with confirmation of Down's Syndrome.

    Reporting group title
    Healthy Volunteers
    Reporting group description
    		 Subjects with no evidence of any eye disease. All results including baseline data are based on the 39 eligible patients.

    Reporting group values
    		 Glaucoma Age-related Macular Degeneration Optic Neuritis Down's Syndrome Healthy Volunteers Total
    Number of subjects
    		 20 19 18 16 40 113
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 12 1 13 16 31 73
        From 65-84 years
    		 8 14 1 0 8 31
        85 years and over
    		 0 4 0 0 0 4
        Ineligible participant
    		 0 0 4 0 1 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.1 ( 13.7 ) 79.9 ( 7.4 ) 45.3 ( 12.1 ) 39.7 ( 7.7 ) 47.6 ( 17.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 9 11 4 21 51
        Male
    		 14 10 3 12 18 57
        Ineligible participant
    		 0 0 4 0 1 5
    Ethnicity
    Units: Subjects
        Caucasian
    		 16 15 10 16 28 85
        Black
    		 3 0 1 0 3 7
        Asian
    		 0 4 1 0 6 11
        Hispanic
    		 0 0 1 0 2 3
        Other
    		 1 0 1 0 0 2
        Ineligible participant
    		 0 0 4 0 1 5
    AMD type
    Units: Subjects
        Early AMD & Late AMD
    		 0 1 0 0 0 1
        Early AMD & Neovascular AMD
    		 0 1 0 0 0 1
        Late AMD
    		 0 3 0 0 0 3
        Neovascular AMD
    		 0 12 0 0 0 12
        Early AMD
    		 0 2 0 0 0 2
        Not applicable
    		 20 0 18 16 40 94
    Glaucoma category
    Units: Subjects
        Glaucoma
    		 8 0 0 0 0 8
        Glaucoma suspect
    		 12 0 0 0 0 12
        Not applicable
    		 0 19 18 16 40 93
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 81.3 ( 17.5 ) 65.8 ( 9.9 ) 74.8 ( 14.3 ) 71.8 ( 18.7 ) 70.0 ( 11.6 ) -
    BMI
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 26.8 ( 4.6 ) 24.9 ( 3.1 ) 26.1 ( 4.7 ) 29.7 ( 5.7 ) 24.0 ( 3.3 ) -
    SBP
    Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 140 ( 17.0 ) 142 ( 17.5 ) 132 ( 18.7 ) 119 ( 15.3 ) 129 ( 14.5 ) -
    DBP
    Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 77.9 ( 10.3 ) 71.4 ( 9.6 ) 73.6 ( 18.7 ) 70.4 ( 8.9 ) 75.8 ( 9.0 ) -
    Heart rate
    Units: beat/min
        arithmetic mean (standard deviation)
    		 69.5 ( 14.0 ) 64.9 ( 9.7 ) 69.0 ( 11.3 ) 65.3 ( 11.1 ) 69.7 ( 9.9 ) -
    Respiratory rate
    Units: breaths/min
        arithmetic mean (standard deviation)
    		 17.0 ( 2.6 ) 16.6 ( 1.4 ) 16.9 ( 1.9 ) 17.3 ( 1.2 ) 16.7 ( 1.9 ) -
    Autofluorescence spot count
    Units: Baseline spot count
        geometric mean (standard deviation)
    		 30.2 ( 1.62 ) 67.5 ( 1.71 ) 30.8 ( 1.39 ) 22.6 ( 1.32 ) 30.2 ( 1.34 ) -
    IOP
    Mean intraocular pressure of eligible eyes.
    Units: mmHg
        arithmetic mean (standard deviation)
    		 18.9 ( 2.6 ) 13.5 ( 3.5 ) 13.9 ( 2.0 ) 0 ( 0 ) 13.6 ( 2.5 ) -
    Corneal pachymetry
    Units: micrometer
        arithmetic mean (standard deviation)
    		 555 ( 33.6 ) 541 ( 37.2 ) 528 ( 40.3 ) 0 ( 0 ) 530 ( 25.8 ) -
    VF mean deviation
    Visual field mean deviation
    Units: dB
        arithmetic mean (standard deviation)
    		 -1.7 ( 2.1 ) 0 ( 0 ) -4.7 ( 5.7 ) 0 ( 0 ) -0.3 ( 1.1 ) -
    Visual acuity
    Units: logmar
        arithmetic mean (standard deviation)
    		 0.01 ( 0.08 ) 0.45 ( 0.9 ) -0.00000001 ( 0.28 ) 0 ( 0 ) -0.03 ( 0.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Glaucoma
    Reporting group description
    		 Subjects with at least one eye with a diagnosis of Glaucoma.

    Reporting group title
    Age-related Macular Degeneration
    Reporting group description
    		 Subjects with Age-related Macular Degeneration (AMD).

    Reporting group title
    Optic Neuritis
    Reporting group description
    		 Subjects with clinical diagnosis of Optic neuritis (ON) affecting one eye within two years. All results including baseline data are based on the 14 eligible patients.

    Reporting group title
    Down's Syndrome
    Reporting group description
    		 Subjects with confirmation of Down's Syndrome.

    Reporting group title
    Healthy Volunteers
    Reporting group description
    		 Subjects with no evidence of any eye disease. All results including baseline data are based on the 39 eligible patients.

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Only those participants who met the eligibility criteria and were not recruited by mistake are included in the analyses.

    Primary: Primary outcome

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    End point title
    		 Primary outcome
    End point description
    Raw DARC counts are taken from imaging of each eligible eye using an automated process built on an algorithm which was developed blind to disease group to ensure an objective measure which is comparable across groups. The cSLO images were background subtracted and standardised before a template matching approach was applied using a 50*50 pixel ‘ideal spot’ template to identify spot candidates. Once identified, spot candidates will be extracted from each cSLO image and spot morphology recorded. An exploratory technique was undertaken to validate an algorithm for differentiating ‘true’ DARC spots amongst candidates. The resulting DARC spots were summed for each eye to yield a ‘weighted’ DARC count. Analysis will be repeated using the ‘weighted’ DARC count produced using the algorithm as exploratory outcome.
    End point type
    Primary
    End point timeframe
    4 hours post injection.
    End point values
    		 Glaucoma Age-related Macular Degeneration Optic Neuritis Down's Syndrome Healthy Volunteers
    Number of subjects analysed
    20 [1]
    19 [2]
    14 [3]
    15 [4]
    39 [5]
    Units: raw DARC counts
        geometric mean (confidence interval 95%)
    42.0 (38.4 to 45.9)
    76.0 (63.5 to 91.0)
    37.1 (29.2 to 47.1)
    30.0 (26.2 to 34.2)
    46.3 (41.7 to 51.4)
    Notes
    [1] - Analysis based on the 38 eligible eyes.
    [2] - Analysis based on the 32 eligible eyes.
    [3] - Analysis based on the 22 eligible eyes.
    [4] - Analysis based on the 30 eligible eyes.
    [5] - Analysis based on the 75 eligible eyes.
    Statistical analysis title
    		 Glaucoma and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between Glaucoma group and healthy volunteers at 4 hours post injection.
    Comparison groups
    Glaucoma v Healthy Volunteers
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.1
    Statistical analysis title
    		 AMD and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between AMD participants and Healthy volunteers at 4 hours post injection.
    Comparison groups
    Age-related Macular Degeneration v Healthy Volunteers
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.27
    Statistical analysis title
    		 ON and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between ON participants and Healthy volunteers at 4 hours post injection.
    Comparison groups
    Optic Neuritis v Healthy Volunteers
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.02
    Statistical analysis title
    		 Down's syndrome and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between Down's syndrome participants and Healthy volunteers at 4 hours post injection.
    Comparison groups
    Down's Syndrome v Healthy Volunteers
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 0.98

    Secondary: Secondary outcome - 2 hours post injection

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    End point title
    		 Secondary outcome - 2 hours post injection
    End point description
    Comparison of raw DARC counts between each of the study groups and Healthy volunteers at 2 hours post injection.
    End point type
    Secondary
    End point timeframe
    2 hours post injection.
    End point values
    		 Glaucoma Age-related Macular Degeneration Optic Neuritis Down's Syndrome Healthy Volunteers
    Number of subjects analysed
    20 [6]
    19 [7]
    14 [8]
    15 [9]
    39 [10]
    Units: Raw DARC count
        geometric mean (confidence interval 95%)
    41.3 (36.6 to 46.5)
    72.9 (59.9 to 88.8)
    48.4 (41.4 to 56.5)
    29.9 (26.5 to 33.8)
    47.0 (42.6 to 52.0)
    Notes
    [6] - Analysis based on the 38 eligible eyes.
    [7] - Analysis based on the 32 eligible eyes.
    [8] - Analysis based on the 22 eligible eyes.
    [9] - Analysis based on the 30 eligible eyes.
    [10] - Analysis based on the 75 eligible eyes.
    Statistical analysis title
    		 Glaucoma and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between Glaucoma group and healthy volunteers at 2 hours post injection.
    Comparison groups
    Glaucoma v Healthy Volunteers
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.06
    Statistical analysis title
    		 AMD and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between AMD group and healthy volunteers at 2 hours post injection.
    Comparison groups
    Age-related Macular Degeneration v Healthy Volunteers
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.27
    Statistical analysis title
    		 ON and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between ON group and healthy volunteers at 2 hours post injection.
    Comparison groups
    Optic Neuritis v Healthy Volunteers
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.09
    Statistical analysis title
    		 Down's syndrome and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between Down's syndrome group and healthy volunteers at 2 hours post injection.
    Comparison groups
    Down's Syndrome v Healthy Volunteers
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 0.96

    Secondary: Secondary outcome - 15 minutes post injection

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    End point title
    		 Secondary outcome - 15 minutes post injection
    End point description
    Comparison of raw DARC counts between each study group and healthy volunteers at 15 minutes post injection.
    End point type
    Secondary
    End point timeframe
    15 minutes post injection.
    End point values
    		 Glaucoma Age-related Macular Degeneration Optic Neuritis Down's Syndrome Healthy Volunteers
    Number of subjects analysed
    20 [11]
    19 [12]
    14 [13]
    15 [14]
    39 [15]
    Units: raw DARC count
        geometric mean (confidence interval 95%)
    33.3 (29.9 to 37.1)
    67.9 (57.2 to 80.6)
    35.9 (30.7 to 42.0)
    27.6 (24.8 to 30.7)
    32.3 (28.9 to 36.1)
    Notes
    [11] - Analysis based on the 38 eligible eyes.
    [12] - Analysis based on the 32 eligible eyes.
    [13] - Analysis based on the 22 eligible eyes.
    [14] - Analysis based on the 30 eligible eyes.
    [15] - Analysis based on the 75 eligible eyes.
    Statistical analysis title
    		 Glaucoma and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between Glaucoma group and healthy volunteers at 15 minutes post injection.
    Comparison groups
    Glaucoma v Healthy Volunteers
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.38
    Statistical analysis title
    		 AMD and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between AMD group and healthy volunteers at 15 minutes post injection
    Comparison groups
    Age-related Macular Degeneration v Healthy Volunteers
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 1.49
    Statistical analysis title
    		 ON and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between ON group and healthy volunteers at 15 minutes post injection
    Comparison groups
    Optic Neuritis v Healthy Volunteers
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.15
    Statistical analysis title
    		 Down's syndrome and Healthy Volunteers
    Statistical analysis description
    Comparison of raw DARC counts between Down's syndrome group and healthy volunteers at 15 minutes post injection.
    Comparison groups
    Down's Syndrome v Healthy Volunteers
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.07

    Other pre-specified: Exploratory analysis - weighted DARC counts

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    End point title
    		 Exploratory analysis - weighted DARC counts [16]
    End point description
    An exploratory technique was undertaken to validate an algorithm for differentiating ‘true’ DARC spots amongst candidates. Spot candidate populations were gated to exclude non-DARC spot objects and artefacts based on spot area (> 10 pixels and < 1000 pixels in size), standard deviation (standardised intensity units > 0.5) and solidity (measure of roundness/ overall concavity) < 0.75). The resulting DARC spots were summed for each eye to yield a ‘weighted’ DARC count.
    End point type
    Other pre-specified
    End point timeframe
    2 hours post injection
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: At present, data are available for the Glaucoma participants and Healthy volunteers only. The same technique will be used to obtain the weighted DARC counts in all the other groups.
    End point values
    		 Glaucoma Healthy Volunteers
    Number of subjects analysed
    18 [17]
    22 [18]
    Units: weighted DARC count
        geometric mean (confidence interval 95%)
    131.4 (97.0 to 177.9)
    98.3 (78.6 to 123.1)
    Notes
    [17] - Analysis based on images of 32 eligible eyes having clear quality for intensity measurements.
    [18] - Analysis based on images of 41 eligible eyes having clear quality for intensity measurements.
    Statistical analysis title
    		 Glaucoma and Healthy Volunteers
    Statistical analysis description
    Comparison of weighted DARC counts between Glaucoma group and healthy volunteers at 2 hours post injection.
    Comparison groups
    Glaucoma v Healthy Volunteers
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 2.02

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Participants (or carer for Down’s syndrome participants) were followed up via telephone call 30 days after administration of IMP to check for any symptoms and/or adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Glaucoma
    Reporting group description
    		 Subjects with at least one eye with a diagnosis of Glaucoma.

    Reporting group title
    Age-related Macular Degeneration
    Reporting group description
    		 Subjects with Age-related Macular Degeneration (AMD).

    Reporting group title
    Optic Neuritis
    Reporting group description
    		 Subjects with clinical diagnosis of Optic neuritis (ON) affecting one eye within two years. All results including baseline data are based on the 14 eligible patients.

    Reporting group title
    Down's Syndrome
    Reporting group description
    		 Subjects with confirmation of Down's Syndrome. All results including baseline data are based on the 15 patients with complete baseline data.

    Reporting group title
    Healthy Volunteers
    Reporting group description
    		 Subjects with no evidence of any eye disease. All results including baseline data are based on the 39 eligible patients.

    Serious adverse events
    		 Glaucoma Age-related Macular Degeneration Optic Neuritis Down's Syndrome Healthy Volunteers
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 40 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Glaucoma Age-related Macular Degeneration Optic Neuritis Down's Syndrome Healthy Volunteers
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 19 (5.26%)
    4 / 18 (22.22%)
    0 / 16 (0.00%)
    3 / 40 (7.50%)
    Nervous system disorders
    Feeling disorientated
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    3
    0
    1
    0
    1
    General disorders and administration site conditions
    Exhaustion/ Lethargy
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    3 / 18 (16.67%)
    0 / 16 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Rash on canula site
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Sore throat
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Problems with balance
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Eye disorders
    Deteriorating eyesight
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Difficulty seeing objects in motion
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Sensitivity to light
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Tired eyes
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Swollen feet
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Nov 2016
    Protocol updated to v3.0 with the following: removal of the Down’s syndrome group and a reduction of the sample size accordingly by 20; general participant exclusion criterion in relation to contraception and pregnancy amended for consistency; inclusion of a table of additional pre-clinical data for DARC; clarifications throughout.
    03 Jan 2017
    Extension of the expiry date of the IMP (ANX776) until 30 June 2017 based on new stability testing data. Updated IMPD.
    20 Apr 2017
    Protocol updated to v4.0 with the following: re-inclusion of a subgroup of 20 participants with Down’s syndrome. This subgroup was originally approved by the MHRA but was removed as the REC requested further scientific and ethical rationale for the inclusion of this subgroup. The rationale is provided in the protocol.
    01 Jun 2017
    Details: Protocol updated to v9.0 with the following: REC requested changes in relation to the inclusion of the participants with Down’s syndrome subgroup; general inclusion criteria edited to remove requirement for best corrected visual acuity equal to 6/24 or better at qualification and to state women of childbearing potential must agree to a pregnancy test instead of consent; removal of the exclusion criteria for age-related macular degeneration subgroup relating to the presence of ocular conditions with increased risk of choroidal neovascularisation. Only those with choroidal neovascularisation will be excluded; removal of the single exclusion criteria for the optic neuritis subgroup; clarifications throughout.

    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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