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    Clinical Trial Results:
    A Phase 3 Multicenter, Randomized, Double-Masked, Sham Controlled Clinical Trial to Assess the Safety and Efficacy of Intravitreal Administration of Zimura (Complement C5 Inhibitor) in Patients with Geographic Atrophy Secondary to Age-Related Macular Degeneration

    Summary
    EudraCT number
    		 2020-000676-38
    Trial protocol
    		 GB   FR   DE   HU   EE   LV   PL   CZ   ES   IT   SK   BE   HR  
    Global end of trial date
    22 Aug 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Dec 2024
    First version publication date
    11 Aug 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ISEE2008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04435366
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc
    Sponsor organisation address
    1 Astellas Way Northbrook, Illinois, United States, 60062
    Public contact
    Clinical Transparency, Astellas Pharma Global Development, Inc, +1 8008887704, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Transparency, Astellas Pharma Global Development, Inc, +1 8008887704, astellas.resultsdisclosure@astellas.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
    22 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to evaluate the safety and efficacy of avacincaptad pegol IVT administration when administered in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jun 2020
    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
    Argentina: 19
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Colombia: 23
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Estonia: 29
    Country: Number of subjects enrolled
    France: 51
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Latvia: 3
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    United States: 181
    Worldwide total number of subjects
    448
    EEA total number of subjects
    184
    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)
    39
    From 65 to 84 years
    320
    85 years and over
    89

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants ≥ 50 years of age diagnosed with GA that was at least partly within 1.5 mm radius from the foveal center were enrolled in the study.

    Pre-assignment
    Screening details
    		 Participants who met all inclusion criteria and none of the exclusion criteria were enrolled in the study.

    Period 1
    Period 1 title
    Year 1 (12 months)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avacincaptad Pegol
    Arm description
    		 Participants received avacincaptad pegol (ACP) 2 milligram (mg)/eye via intravitreal (IVT) injections monthly through Month 11 (Year 1). At month 12, participants were re-randomized to receive ACP 2 mg/eye via IVT injections monthly from month12 through month 23 (Year 2). Participants were followed up until month 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avacincaptad pegol
    Investigational medicinal product code
    ARC1905
    Other name
    Zimura (previous name) IZERVAY
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2 mg/eye via IVT injections

    Arm title
    		 Sham
    Arm description
    		 Participants received sham injections; through Month 11 (Year 1). At month 12, participants continued to receive monthly sham injection from month 12 through month 23 (Year 2). Participants were followed up until month 24.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sham
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    IVT injections

    Number of subjects in period 1
    		Avacincaptad Pegol Sham
    Started
    225
    223
    Treated
    225
    222
    Completed
    200
    205
    Not completed
    25
    18
         Adverse event, serious fatal
    2
    1
         Consent withdrawn by subject
    17
    13
         Adverse event, non-fatal
    3
    2
         Patient non-compliance
    1
    -
         Lost to follow-up
    2
    1
         Not treated
    -
    1
    Period 2
    Period 2 title
    Year 2 (12 months)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avacincaptad Pegol
    Arm description
    		 Participants received avacincaptad pegol (ACP) 2 milligram (mg)/eye via intravitreal (IVT) injections monthly through Month 11 (Year 1). At month 12, participants were re-randomized to receive ACP 2 mg/eye via IVT injections monthly from month12 through month 23 (Year 2). Participants were followed up until month 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avacincaaptad pegol
    Investigational medicinal product code
    ARC1905
    Other name
    Zimura (previous name) IZERVAY
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2 mg/eye via IVT injections

    Arm title
    		 Avacincaptad pegol and Sham
    Arm description
    		 Participants received ACP 2 mg/eye via IVT injections monthly through Month 11 (Year 1). At month 12, participants were re-randomized to receive ACP 2 mg/eye via IVT every other month (EOM) at months 13, 15, 17, 19, 21, and 23 and sham injections at months 12, 14, 16,18, 20, and 22 (Year 2). Participants were followed up until month 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avacincaptad pegol
    Investigational medicinal product code
    ARC1905
    Other name
    Zimura (previous name) IZERVAY
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2 mg/eye via IVT injections

    Arm title
    		 Sham
    Arm description
    		 Participants received sham injections; through Month 11 (Year 1). At month 12, participants continued to receive monthly sham injection from month 12 through month 23 (Year 2). Participants were followed up until month 24.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sham
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    IVT injections

    Number of subjects in period 2 [1]
    		Avacincaptad Pegol Avacincaptad pegol and Sham Sham
    Started
    96
    93
    203
    Completed
    89
    83
    184
    Not completed
    7
    10
    19
         Adverse event, serious fatal
    1
    4
    6
         Consent withdrawn by subject
    4
    3
    7
         Adverse event, non-fatal
    2
    1
    6
         Lost to follow-up
    -
    2
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The participants were further divided into three arms in period 2, hence the participants that completed the first period do not match the participants that started period 2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Avacincaptad Pegol
    Reporting group description
    		 Participants received avacincaptad pegol (ACP) 2 milligram (mg)/eye via intravitreal (IVT) injections monthly through Month 11 (Year 1). At month 12, participants were re-randomized to receive ACP 2 mg/eye via IVT injections monthly from month12 through month 23 (Year 2). Participants were followed up until month 24.

    Reporting group title
    Sham
    Reporting group description
    		 Participants received sham injections; through Month 11 (Year 1). At month 12, participants continued to receive monthly sham injection from month 12 through month 23 (Year 2). Participants were followed up until month 24.

    Reporting group values
    		 Avacincaptad Pegol Sham Total
    Number of subjects
    		 225 223
    Age categorical
    Units: Participants
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 76.3 ( 8.6 ) 76.7 ( 8.8 ) -
    Sex
    Units: Participants
        Female
    		 154 156 310
        Male
    		 71 67 138
    Ethnicity
    Units: Subjects
        HISPANIC OR LATINO
    		 27 23 50
        NOT HISPANIC OR LATINO
    		 168 179 347
        NOT REPORTED
    		 30 21 51
    Race
    Units: Subjects
        AMERICAN INDIAN OR ALASKA NATIVE
    		 1 0 1
        ASIAN
    		 1 1 2
        BLACK OR AFRICAN AMERICAN
    		 0 1 1
        NOT REPORTED
    		 31 21 52
        More than one race
    		 10 13 23
        WHITE
    		 182 187 369

    End points

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    End points reporting groups
    Reporting group title
    Avacincaptad Pegol
    Reporting group description
    		 Participants received avacincaptad pegol (ACP) 2 milligram (mg)/eye via intravitreal (IVT) injections monthly through Month 11 (Year 1). At month 12, participants were re-randomized to receive ACP 2 mg/eye via IVT injections monthly from month12 through month 23 (Year 2). Participants were followed up until month 24.

    Reporting group title
    Sham
    Reporting group description
    		 Participants received sham injections; through Month 11 (Year 1). At month 12, participants continued to receive monthly sham injection from month 12 through month 23 (Year 2). Participants were followed up until month 24.
    Reporting group title
    Avacincaptad Pegol
    Reporting group description
    		 Participants received avacincaptad pegol (ACP) 2 milligram (mg)/eye via intravitreal (IVT) injections monthly through Month 11 (Year 1). At month 12, participants were re-randomized to receive ACP 2 mg/eye via IVT injections monthly from month12 through month 23 (Year 2). Participants were followed up until month 24.

    Reporting group title
    Avacincaptad pegol and Sham
    Reporting group description
    		 Participants received ACP 2 mg/eye via IVT injections monthly through Month 11 (Year 1). At month 12, participants were re-randomized to receive ACP 2 mg/eye via IVT every other month (EOM) at months 13, 15, 17, 19, 21, and 23 and sham injections at months 12, 14, 16,18, 20, and 22 (Year 2). Participants were followed up until month 24.

    Reporting group title
    Sham
    Reporting group description
    		 Participants received sham injections; through Month 11 (Year 1). At month 12, participants continued to receive monthly sham injection from month 12 through month 23 (Year 2). Participants were followed up until month 24.

    Primary: The mean rate of growth (slope) estimated based on GA area measured by autofluorescence (FAF) at 3 time points: Baseline, Month 6, and Month 12

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    End point title
    		 The mean rate of growth (slope) estimated based on GA area measured by autofluorescence (FAF) at 3 time points: Baseline, Month 6, and Month 12
    End point description
    GA was associated with age-related macular degeneration (AMD) and caused bilateral, progressive, and irreversible loss of retinal tissue (photoreceptors, retinal pigment epithelium, and choriocapillaris) leading to a permanent loss of visual function and blindness. The least squares mean used to determine mean rate of change in GA growth (slope) was measured by FAF. LS mean & SE were based on square-root transformation. Intent to Treat (ITT) analysis set consisted of all randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline to month 12
    End point values
    		 Avacincaptad Pegol Sham
    Number of subjects analysed
    225
    222
    Units: millimeters (mm)/year
        least squares mean (standard error)
    0.336 ( 0.032 )
    0.392 ( 0.033 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Difference in least squares mean between groups calculated as (sham) minus (avacincaptad pegol). Mixed Model for repeated measures (MMRM) was used to compare the treatment groups.
    Comparison groups
    Sham v Avacincaptad Pegol
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0064 [1]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.016
         upper limit
    		 0.096
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Notes
    [1] - Nominal p-value was used for the comparison between avacincaptad pegol versus sham.

    Primary: The mean rate of growth (slope) estimated based on GA area measured by FAF at 5 timepoints: Baseline, Month 6, Month 12, Month 18, and Month 24

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    End point title
    		 The mean rate of growth (slope) estimated based on GA area measured by FAF at 5 timepoints: Baseline, Month 6, Month 12, Month 18, and Month 24
    End point description
    GA was associated with AMD and caused bilateral, progressive, and irreversible loss of retinal tissue (photoreceptors, retinal pigment epithelium, and choriocapillaris) leading to a permanent loss of visual function and blindness. The least square mean rate of GA growth (slope) was measured by FAF. LS mean & SE were based on untransformed data. Re-randomized (Re-rand) analysis set- the subset of the ITT analysis set who were re-randomized at month 12 and who were on sham and completed the month 12 visit. Re-rand analysis set-The subset of the ITT analysis set who were re-randomized at Month 12 and who were on sham and completed the Month 12 visit
    End point type
    Primary
    End point timeframe
    Baseline to month 24
    End point values
    		 Avacincaptad Pegol Avacincaptad pegol and Sham Sham
    Number of subjects analysed
    96
    93
    203
    Units: mm^2/year
        least squares mean (standard error)
    2.23 ( 0.124 )
    2.10 ( 0.126 )
    2.59 ( 0.085 )
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Difference in least squares mean between groups calculated as (sham) minus (avacincaptad pegol and sham).
    Comparison groups
    Avacincaptad pegol and Sham v Sham
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015 [2]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.488
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.189
         upper limit
    		 0.788
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.152
    Notes
    [2] - Nominal p-value was used for the comparison between avacincaptad pegol and sham versus sham
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Difference in least squares mean between groups calculated as (sham) minus (avacincaptad pegol).
    Comparison groups
    Avacincaptad Pegol v Sham
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0165 [3]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.362
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.066
         upper limit
    		 0.657
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [3] - Nominal p-value was used for the comparison between avacincaptad pegol versus sham.

    Secondary: Change from Baseline in Best Corrected Visual Acuity (BCVA) using early treatment diabetic retinopathy study (ETDRS) letters at 24 months

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    End point title
    		 Change from Baseline in Best Corrected Visual Acuity (BCVA) using early treatment diabetic retinopathy study (ETDRS) letters at 24 months
    End point description
    BCVA was assessed using ETDRS visual acuity testing charts. The ETDRS Visual Acuity Score (VAS) is defined as the number of letters read on the ETDRS chart. Minimum and maximum possible scores are 0-100. A higher score represented better visual functioning. A positive change from baseline indicates an improvement and a negative change from baseline indicates a worsening. ITT analysis set
    End point type
    Secondary
    End point timeframe
    Baseline and month 24
    End point values
    		 Avacincaptad Pegol Sham
    Number of subjects analysed
    225
    222
    Units: score on a scale
        least squares mean (standard error)
    -7.31 ( 1.07 )
    -6.48 ( 1.05 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Difference in least squares mean between groups calculated as (sham) minus (avacincaptad pegol).
    Comparison groups
    Avacincaptad Pegol v Sham
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58 [4]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.79
         upper limit
    		 2.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.5
    Notes
    [4] - Nominal p-value was used for the comparison between avacincaptad pegol versus sham.

    Secondary: Change from Baseline in Low Luminance (LL) BCVA using ETDRS letters at 24 months

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    End point title
    		 Change from Baseline in Low Luminance (LL) BCVA using ETDRS letters at 24 months
    End point description
    BCVA was assessed using ETDRS visual acuity testing charts. The ETDRS VAS is defined as the number of letters read on the ETDRS chart. Minimum and maximum possible scores are 0-100. A higher score represented better visual functioning. A positive change from baseline indicates an improvement and a negative change from baseline indicates a worsening. LL BCVA was measured by placing a 2.0 log unit neutral density filter over the best correction for that eye and having the participant read the normally illuminated ETDRS chart. ITT analysis set
    End point type
    Secondary
    End point timeframe
    Baseline and month 24
    End point values
    		 Avacincaptad Pegol Sham
    Number of subjects analysed
    225
    222
    Units: score on a scale
        least squares mean (standard error)
    -10.58 ( 1.20 )
    -9.10 ( 1.18 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Difference in least squares mean between groups calculated as (sham) minus (avacincaptad pegol).
    Comparison groups
    Avacincaptad Pegol v Sham
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38 [5]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.79
         upper limit
    		 1.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.68
    Notes
    [5] - Nominal p-value was used for the comparison between avacincaptad pegol versus sham.

    Secondary: Change from Baseline in Visual Function Questionnaire (VFQ-25) Composite Scores at 6,12 and 18 months

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    End point title
    		 Change from Baseline in Visual Function Questionnaire (VFQ-25) Composite Scores at 6,12 and 18 months
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (VFQ-25) measured the influence of visual disability and visual symptoms on general health domains. The VFQ-25 consisted of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. A higher score represented better visual functioning. Each item was then converted to a 0 to 100 scale so that the lowest and highest possible scores were set at 0 and 100 points, respectively. Each subscale score had a range of 0 to 100 inclusive and were calculated from the re-scaled raw data. A composite score was derived based on the average of the 11 vision-related subscales. ITT analysis set with available data was analyzed
    End point type
    Secondary
    End point timeframe
    Baseline, months 6, 12 and 18
    End point values
    		 Avacincaptad Pegol Sham
    Number of subjects analysed
    206
    215
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at 6 months (n = 206, 215)
    -1.2 ( 10.56 )
    -1.6 ( 9.98 )
        Change at 12 months (n = 196,199)
    -3.4 ( 11.05 )
    -3.6 ( 11.01 )
        Change at 18 months (n = 173,187)
    -5.4 ( 12.80 )
    -4.7 ( 11.53 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Visual Function Questionnaire (VFQ-25) Composite Scores at 24 months

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    End point title
    		 Change from Baseline in Visual Function Questionnaire (VFQ-25) Composite Scores at 24 months
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (VFQ-25) measured the influence of visual disability and visual symptoms on general health domains. The VFQ-25 consisted of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. A higher score represented better visual functioning. Each item was then converted to a 0 to 100 scale so that the lowest and highest possible scores were set at 0 and 100 points, respectively. Each subscale score had a range of 0 to 100 inclusive and were calculated from the re-scaled raw data. A composite score was derived based on the average of the 11 vision-related subscales. ITT analysis set
    End point type
    Secondary
    End point timeframe
    Baseline and month 24
    End point values
    		 Avacincaptad Pegol Sham
    Number of subjects analysed
    225
    222
    Units: score on a scale
        least squares mean (standard error)
    -7.735 ( 0.950 )
    -7.023 ( 0.931 )
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Avacincaptad Pegol v Sham
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5929
    Method
    		 MMRM
    Parameter type
    		 Least square mean difference
    Point estimate
    -0.712
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.326
         upper limit
    		 1.903
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.33

    Secondary: Number of Participants with Categorical one-level loss in VFQ-25 Subscale

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    End point title
    		 Number of Participants with Categorical one-level loss in VFQ-25 Subscale
    End point description
    The National Eye Institute VFQ-25 measured the influence of visual disability and visual symptoms on general health domains. The VFQ-25 consisted of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. A higher score represented better visual functioning. Each item was then converted to a 0 to 100 scale so that the lowest and highest possible scores were set at 0 and 100 points, respectively.Categorical one-level loss in each item was defined as decline of one or more levels at Month 24 on the original scale from Baseline (equivalently 20 points for general vision and 25 points for other vision items in a 0 to 100 scale). ITT analysis set with available data was analyzed
    End point type
    Secondary
    End point timeframe
    Baseline up to month 24
    End point values
    		 Avacincaptad Pegol Sham
    Number of subjects analysed
    175
    182
    Units: participants
        Color Vision
    45
    35
        Distance Vision
    56
    43
        Near Vision
    61
    49
        Peripheral Vision
    58
    65
        General Vision
    58
    58
        Dependency
    55
    55
        Driving
    27
    26
        General Health
    45
    67
        Mental Health
    35
    42
        Ocular Pain
    27
    20
        Role Difficulties
    60
    59
        Social Function
    52
    52
    No statistical analyses for this end point

    Secondary: Time to Persistent Vision Loss

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    End point title
    		 Time to Persistent Vision Loss
    End point description
    Vision loss event was defined as a loss of ≥ 15 letters (equivalent to a loss of 3 lines on the ETDRS chart) in BCVA from Baseline measured at any two or more consecutive visits up to Month 24. These parameters were chosen as a 3-line BCVA loss (equivalent to doubling of visual angle) is widely recognized as a significant deterioration in vision and a minimum of two consecutive visits was representative of persistent disease progression. BCVA was assessed using ETDRS visual acuity testing charts. The ETDRS VAS was defined as the number of letters read on the ETDRS chart. Min and max possible scores are 0-100. A higher score represents better visual functioning. Kaplan-Meier method was used for analysis. Participants with an event were reported and not the median time to event. ITT analysis set
    End point type
    Secondary
    End point timeframe
    Baseline up to month 24
    End point values
    		 Avacincaptad Pegol Sham
    Number of subjects analysed
    225
    222
    Units: months
        median (full range (min-max))
    17.02 (2.8 to 23.0)
    13.93 (1.3 to 23.2)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Avacincaptad Pegol v Sham
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6424
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.42

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose up to 24 months
    Adverse event reporting additional description
    ACM: All randomized participants. Serious & non-SAEs: Those who received at least 1 dose of treatment. Those who received injection of ACP were analyzed in ACP group according to actual injections. 1 participant randomized to sham didn’t receive treatment & was included in denominator for ACM only & not for other outcomes.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    v24.1
    Reporting groups
    Reporting group title
    Avacincaptad Pegol only (up to 12 months)
    Reporting group description
    		 Participants received ACP 2 mg/eye via IVT injections monthly through Month 11 (Year 1).

    Reporting group title
    Avacincaptad Pegol only (12 to 24 months)
    Reporting group description
    		 Participants were re-randomized at month 12 to receive ACP 2 mg/eye via IVT injections monthly from month 12 through month 23 (Year 2). Participants were followed up until month 24.

    Reporting group title
    Sham only (12 to 24 months)
    Reporting group description
    		 Participants continued to receive monthly sham injection from month 12 through month 23 (Year 2). Participants were followed up until month 24.

    Reporting group title
    Sham only (up to 12 months)
    Reporting group description
    		 Participants received sham injections through Month 11 (Year 1).

    Reporting group title
    Avacincaptad Pegol and Sham only (12 to 24 months)
    Reporting group description
    		 Participants were re-randomized at month 12, to receive ACP 2 mg/eye via IVT injections every other month at months 13, 15, 17, 19, 21, and 23 and sham injections at months 12, 14, 16,18, 20, and 22 (Year 2). Participants were followed up until month 24.

    Serious adverse events
    		 Avacincaptad Pegol only (up to 12 months) Avacincaptad Pegol only (12 to 24 months) Sham only (12 to 24 months) Sham only (up to 12 months) Avacincaptad Pegol and Sham only (12 to 24 months)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 225 (13.78%)
    18 / 96 (18.75%)
    25 / 203 (12.32%)
    36 / 222 (16.22%)
    16 / 93 (17.20%)
         number of deaths (all causes)
    4
    1
    7
    1
    4
         number of deaths resulting from adverse events
    2
    1
    5
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute leukaemia
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinonasal papilloma
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer stage IIIA
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    2 / 222 (0.90%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurogenic shock
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 225 (0.89%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device lead damage
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exposure to toxic agent
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Mobile caecum syndrome
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    2 / 203 (0.99%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 225 (0.89%)
    1 / 96 (1.04%)
    2 / 203 (0.99%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    2 / 203 (0.99%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    2 / 203 (0.99%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    3 / 203 (1.48%)
    1 / 222 (0.45%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    2 / 203 (0.99%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    2 / 222 (0.90%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    1 / 203 (0.49%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuromyelitis optica spectrum disorder
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Normocytic anaemia
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choroidal neovascularisation
         subjects affected / exposed
    2 / 225 (0.89%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced transiently
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Barrett's oesophagus
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    2 / 203 (0.99%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    2 / 222 (0.90%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis bacterial
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis intestinal perforated
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Listeria sepsis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    1 / 222 (0.45%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 225 (0.89%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    2 / 222 (0.90%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    0 / 203 (0.00%)
    2 / 222 (0.90%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 96 (0.00%)
    1 / 203 (0.49%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 96 (1.04%)
    0 / 203 (0.00%)
    0 / 222 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Avacincaptad Pegol only (up to 12 months) Avacincaptad Pegol only (12 to 24 months) Sham only (12 to 24 months) Sham only (up to 12 months) Avacincaptad Pegol and Sham only (12 to 24 months)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    100 / 225 (44.44%)
    51 / 96 (53.13%)
    77 / 203 (37.93%)
    83 / 222 (37.39%)
    41 / 93 (44.09%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    22 / 225 (9.78%)
    9 / 96 (9.38%)
    1 / 203 (0.49%)
    4 / 222 (1.80%)
    5 / 93 (5.38%)
         occurrences all number
    43
    18
    1
    5
    7
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    14 / 225 (6.22%)
    9 / 96 (9.38%)
    12 / 203 (5.91%)
    17 / 222 (7.66%)
    8 / 93 (8.60%)
         occurrences all number
    15
    9
    17
    18
    8
    Eye disorders
    Choroidal neovascularisation
         subjects affected / exposed
    21 / 225 (9.33%)
    11 / 96 (11.46%)
    19 / 203 (9.36%)
    11 / 222 (4.95%)
    8 / 93 (8.60%)
         occurrences all number
    21
    13
    21
    13
    8
    Cataract
         subjects affected / exposed
    6 / 225 (2.67%)
    7 / 96 (7.29%)
    10 / 203 (4.93%)
    9 / 222 (4.05%)
    4 / 93 (4.30%)
         occurrences all number
    8
    8
    13
    13
    5
    Conjunctival haemorrhage
         subjects affected / exposed
    31 / 225 (13.78%)
    14 / 96 (14.58%)
    5 / 203 (2.46%)
    18 / 222 (8.11%)
    9 / 93 (9.68%)
         occurrences all number
    55
    22
    8
    32
    16
    Punctate keratitis
         subjects affected / exposed
    14 / 225 (6.22%)
    5 / 96 (5.21%)
    5 / 203 (2.46%)
    15 / 222 (6.76%)
    5 / 93 (5.38%)
         occurrences all number
    25
    8
    14
    32
    6
    Conjunctival hyperaemia
         subjects affected / exposed
    12 / 225 (5.33%)
    1 / 96 (1.04%)
    5 / 203 (2.46%)
    13 / 222 (5.86%)
    1 / 93 (1.08%)
         occurrences all number
    34
    1
    6
    38
    1
    Retinal haemorrhage
         subjects affected / exposed
    8 / 225 (3.56%)
    2 / 96 (2.08%)
    2 / 203 (0.99%)
    5 / 222 (2.25%)
    5 / 93 (5.38%)
         occurrences all number
    9
    2
    3
    5
    6
    Infections and infestations
    COVID-19
         subjects affected / exposed
    7 / 225 (3.11%)
    11 / 96 (11.46%)
    26 / 203 (12.81%)
    7 / 222 (3.15%)
    14 / 93 (15.05%)
         occurrences all number
    7
    11
    27
    7
    14
    Nasopharyngitis
         subjects affected / exposed
    4 / 225 (1.78%)
    4 / 96 (4.17%)
    3 / 203 (1.48%)
    6 / 222 (2.70%)
    6 / 93 (6.45%)
         occurrences all number
    4
    6
    3
    8
    6
    Urinary tract infection
         subjects affected / exposed
    14 / 225 (6.22%)
    3 / 96 (3.13%)
    18 / 203 (8.87%)
    13 / 222 (5.86%)
    2 / 93 (2.15%)
         occurrences all number
    17
    3
    22
    13
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2020
    Amendment contained clarifications on assessments, inclusion/exclusion criteria, and pregnancy urine/serum samples.
    18 Dec 2020
    Amendment added monthly optical coherence tomography, clarification on assessments, and inclusion/exclusion criteria.
    24 May 2021
    Amendment clarified the primary endpoint and analysis and minor administrative items.

    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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    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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