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    Clinical Trial Results:
    A Phase 2, Randomized, Placebo-controlled, Double-masked Study to Assess Safety and Efficacy of Multiple Doses of IONIS-FB-LRX, an Antisense Inhibitor of Complement Factor B, in Patients With Geographic Atrophy Secondary to Age-related Macular Degeneration (AMD)

    Summary
    EudraCT number
    		 2020-005174-94
    Trial protocol
    		 CZ   NL   ES   AT  
    Global end of trial date
    12 Jun 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jun 2025
    First version publication date
    29 Jun 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS 696844-CS5
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03815825
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, United States, 92010
    Public contact
    Ionis Pharmaceuticals, Inc., Ionis Clinical Trial Information, +1 760-603-2346, globalregulatoryaffairs@ionis.com
    Scientific contact
    Ionis Pharmaceuticals, Inc., Ionis Clinical Trial Information, +1 760-603-2346, globalregulatoryaffairs@ionis.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
    12 Jun 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Apr 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of this study was to evaluate the effect of IONIS-FB-LRX (ISIS 696844) on the rate of change of the area of geographic atrophy (GA) secondary to age-related macular degeneration (AMD) measured by fundus autofluorescence (FAF).
    Protection of trial subjects
    Each subject, or legally acceptable representative, signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Mar 2019
    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
    United States: 210
    Country: Number of subjects enrolled
    Australia: 38
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    Czechia: 19
    Country: Number of subjects enrolled
    Poland: 16
    Worldwide total number of subjects
    329
    EEA total number of subjects
    67
    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)
    28
    From 65 to 84 years
    244
    85 years and over
    57

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 79 investigative sites in the United States (US), Australia, Spain, Canada, Austria, Poland, and the Czech Republic from 04 March 2019 to 12 June 2024.

    Pre-assignment
    Screening details
    		 A total of 332 subjects with GA secondary to AMD were randomised and 329 received at least 1 dose of either ISIS 696844 or placebo. As pre-specified, for purposes of analyses, data for placebo subjects were pooled for comparison to ISIS 696844-treated subjects. Number reported are the subjects who completed the treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ISIS 696844 40 mg
    Arm description
    		 Subjects received a loading dose of ISIS 696844, 40 milligrams (mg), subcutaneously (SC) at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose every 4 weeks up to Week 45.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 696844
    Investigational medicinal product code
    Other name
    IONIS-FB-LRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ISIS 696844, 40 mg, was administered SC at Weeks 1, 3, and 5 (on Days 1, 15 and 29), followed by 1 dose, Q4W up to Week 45.

    Arm title
    		 ISIS 696844 70 mg
    Arm description
    		 Subjects received a loading dose of ISIS 696844, 70 mg, SC at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose, every 4 weeks up to Week 45.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 696844
    Investigational medicinal product code
    Other name
    IONIS-FB-LRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ISIS 696844, 70 mg, was administered SC at Weeks 1, 3, and 5 (on Days 1, 15 and 29), followed by 1 dose, Q4W up to Week 45.

    Arm title
    		 ISIS 696844 100 mg
    Arm description
    		 Subjects received a loading dose of ISIS 696844, 100 mg, SC at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose, every 4 weeks up to Week 45.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 696844
    Investigational medicinal product code
    Other name
    IONIS-FB-LRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ISIS 696844, 100 mg, was administered SC at Weeks 1, 3, and 5 (on Days 1, 15 and 29), followed by 1 dose, Q4W up to Week 45.

    Arm title
    		 Pooled Placebo
    Arm description
    		 Subjects received matching placebo, either 40 mg, 70 mg, or 100 mg, SC at Weeks 1,3 and 5 (on Days 1, 15, and 29), followed by 1 dose, every 4 weeks up to Week 45.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo, either 40 mg, 70 mg, or 100 mg, was administered SC at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose, Q4W up to Week 45.

    Number of subjects in period 1
    		ISIS 696844 40 mg ISIS 696844 70 mg ISIS 696844 100 mg Pooled Placebo
    Started
    104
    105
    14
    106
    Completed
    92
    96
    14
    97
    Not completed
    12
    9
    0
    9
         Consent withdrawn by subject
    3
    3
    -
    3
         Reason Not Specified
    2
    -
    -
    -
         Ineligibility
    1
    -
    -
    -
         Adverse Event or Serious Adverse Event
    6
    6
    -
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ISIS 696844 40 mg
    Reporting group description
    		 Subjects received a loading dose of ISIS 696844, 40 milligrams (mg), subcutaneously (SC) at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose every 4 weeks up to Week 45.

    Reporting group title
    ISIS 696844 70 mg
    Reporting group description
    		 Subjects received a loading dose of ISIS 696844, 70 mg, SC at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose, every 4 weeks up to Week 45.

    Reporting group title
    ISIS 696844 100 mg
    Reporting group description
    		 Subjects received a loading dose of ISIS 696844, 100 mg, SC at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose, every 4 weeks up to Week 45.

    Reporting group title
    Pooled Placebo
    Reporting group description
    		 Subjects received matching placebo, either 40 mg, 70 mg, or 100 mg, SC at Weeks 1,3 and 5 (on Days 1, 15, and 29), followed by 1 dose, every 4 weeks up to Week 45.

    Reporting group values
    		 ISIS 696844 40 mg ISIS 696844 70 mg ISIS 696844 100 mg Pooled Placebo Total
    Number of subjects
    		 104 105 14 106
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 76.2 ( 8.20 ) 75.6 ( 8.37 ) 72.3 ( 6.90 ) 77.6 ( 8.17 ) -
    Gender categorical
    Units: Subjects
        Male
    		 37 41 8 47 133
        Female
    		 67 64 6 59 196
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 1 0 2 5
        Not Hispanic or Latino
    		 102 104 14 104 324
    Race
    Units: Subjects
        White
    		 102 103 14 106 325
        Black
    		 0 1 0 0 1
        Other Race
    		 2 1 0 0 3
    GA Area Measured by FAF in Study Eye at Baseline
    Baseline was defined as the average of Week -2 (Screening Period 2) and Week 1 (Day 1 pre-dose) assessments.
    Units: square millimeters (mm2)/365.25 days
        arithmetic mean (standard deviation)
    		 7.4498 ( 4.1358 ) 7.7186 ( 3.8793 ) 8.4266 ( 3.9372 ) 7.6762 ( 4.1123 ) -

    End points

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    End points reporting groups
    Reporting group title
    ISIS 696844 40 mg
    Reporting group description
    		 Subjects received a loading dose of ISIS 696844, 40 milligrams (mg), subcutaneously (SC) at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose every 4 weeks up to Week 45.

    Reporting group title
    ISIS 696844 70 mg
    Reporting group description
    		 Subjects received a loading dose of ISIS 696844, 70 mg, SC at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose, every 4 weeks up to Week 45.

    Reporting group title
    ISIS 696844 100 mg
    Reporting group description
    		 Subjects received a loading dose of ISIS 696844, 100 mg, SC at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose, every 4 weeks up to Week 45.

    Reporting group title
    Pooled Placebo
    Reporting group description
    		 Subjects received matching placebo, either 40 mg, 70 mg, or 100 mg, SC at Weeks 1,3 and 5 (on Days 1, 15, and 29), followed by 1 dose, every 4 weeks up to Week 45.

    Primary: Mean Rate of Change From Baseline in GA Area at Week 49 by FAF - Study Eye

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    End point title
    		 Mean Rate of Change From Baseline in GA Area at Week 49 by FAF - Study Eye
    End point description
    The mean rate of change in GA growth was measured by FAF images as determined by the central reading center (CRC). Intent-to-treat (ITT) population included all subjects who were randomized and received at least one dose of the study drug. Baseline was defined as value at Week -2 (Screening Period 2), if available. Otherwise, the last available measurement prior to the first dose will be used as the baseline. As pre-specified, for purposes of analyses, data for placebo subjects were pooled for comparison to ISIS 696844-treated subjects. CNV = choroidal neovascularization.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49
    End point values
    		 ISIS 696844 40 mg ISIS 696844 70 mg ISIS 696844 100 mg Pooled Placebo
    Number of subjects analysed
    104
    105
    14
    106
    Units: mm2/365.25 days
        least squares mean (standard error)
    1.9375 ( 0.1316 )
    2.1059 ( 0.1278 )
    2.0139 ( 0.3448 )
    2.1885 ( 0.1271 )
    Statistical analysis title
    		 ISIS 696844 40 mg vs Pooled Placebo
    Statistical analysis description
    Random effects model with treatment group, interaction between treatment group & time, stage of subjects randomized, status of exudative CNV in fellow eye as factors & time & rate of change in the GA area during screening as covariates. Random effects include the intercept and slope (time) with an unstructured covariance matrix, with all other variables as fixed effects. The within patient error was assumed to be independent and normally distributed with variance component as the covariance stru
    Comparison groups
    ISIS 696844 40 mg v Pooled Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.171
    Method
    		 Random Effect Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.251
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.611
         upper limit
    		 0.1091
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.183
    Statistical analysis title
    		 ISIS 696844 100 mg vs Pooled Placebo
    Statistical analysis description
    Random effects model with treatment group, interaction between treatment group & time, stage of subjects randomized, status of exudative CNV in fellow eye as factors & time & rate of change in the GA area during screening as covariates. Random effects include the intercept & slope (time) with an unstructured covariance matrix with all other variables as fixed effects. The within patient error was assumed to be independent & normally distributed with variance component as the covariance structure
    Comparison groups
    ISIS 696844 100 mg v Pooled Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.635
    Method
    		 Random Effect Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.1745
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8976
         upper limit
    		 0.5486
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3675
    Statistical analysis title
    		 ISIS 696844 70 mg vs Pooled Placebo
    Statistical analysis description
    Random effects model with treatment group, interaction between treatment group & time, stage of subjects randomized, status of exudative CNV in fellow eye as factors & time & rate of change in the GA area during screening as covariates. Random effects include the intercept & slope (time) with an unstructured covariance matrix with all other variables as fixed effects. The within patient error was assumed to be independent & normally distributed with variance component as the covariance structure
    Comparison groups
    ISIS 696844 70 mg v Pooled Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.647
    Method
    		 Random Effect Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.0826
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4372
         upper limit
    		 0.2721
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1802

    Secondary: Absolute Change From Baseline in the GA Area as Measured by FAF - Study Eye

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    End point title
    		 Absolute Change From Baseline in the GA Area as Measured by FAF - Study Eye
    End point description
    The absolute change in GA area was measured by FAF images as determined by the CRC. ITT population included all subjects who were randomized and received at least one dose of the study drug. Subjects analyzed are the number of subjects in ITT population. As pre-specified, for purposes of analyses, data for placebo subjects were pooled for comparison to ISIS 696844-treated subjects. MMRM = Mixed Model for Repeated Measures.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 57
    End point values
    		 ISIS 696844 40 mg ISIS 696844 70 mg ISIS 696844 100 mg Pooled Placebo
    Number of subjects analysed
    104
    105
    14
    106
    Units: mm2
        least squares mean (standard error)
    2.2528 ( 0.1476 )
    2.3590 ( 0.1422 )
    2.3548 ( 0.3753 )
    2.4539 ( 0.1433 )
    Statistical analysis title
    		 ISIS 696844 40 mg vs Pooled Placebo
    Statistical analysis description
    MMRM with treatment group, study visit, interaction between treatment group & study visit, baseline GA area, rate of change in GA area during Screening, stage of subjects randomized & status of exudative CNV in fellow eye as independent variables. An unstructured covariance matrix was used to model the within-subject errors.
    Comparison groups
    ISIS 696844 40 mg v Pooled Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.312
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.201
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5914
         upper limit
    		 0.1894
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1983
    Statistical analysis title
    		 ISIS 696844 100 mg vs Pooled Placebo
    Statistical analysis description
    MMRM with treatment group, study visit, interaction between treatment group & study visit, baseline GA area, rate of change in GA area during Screening, stage of subjects randomized & status of exudative CNV in fellow eye as independent variables. An unstructured covariance matrix was used to model the within-subject errors.
    Comparison groups
    ISIS 696844 100 mg v Pooled Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.806
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.099
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8926
         upper limit
    		 0.6945
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4032
    Statistical analysis title
    		 ISIS 696844 70 mg vs Pooled Placebo
    Statistical analysis description
    MMRM with treatment group, study visit, interaction between treatment group & study visit, baseline GA area, rate of change in GA area during Screening, stage of subjects randomized & status of exudative CNV in fellow eye as independent variables. An unstructured covariance matrix was used to model the within-subject errors.
    Comparison groups
    ISIS 696844 70 mg v Pooled Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.627
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.0948
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.478
         upper limit
    		 0.2884
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1947

    Secondary: Percent Change From Baseline in Levels of Factor B (FB) in Plasma at Steady State

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    End point title
    		 Percent Change From Baseline in Levels of Factor B (FB) in Plasma at Steady State
    End point description
    ITT population included all subjects who were randomized and received at least one dose of the study drug. Baseline was defined as the average of Week -2 (Screening Period 2) and Week 1 (Day 1 pre-dose) assessments. Steady-state levels of complement factors or complement activity were defined as the average of available data from Week 33 to Week 49 assessments. As pre-specified, for purposes of analyses, data for placebo subjects were pooled for comparison to ISIS 696844-treated subjects. ANCOVA = Analysis of Covariance.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    		 ISIS 696844 40 mg ISIS 696844 70 mg ISIS 696844 100 mg Pooled Placebo
    Number of subjects analysed
    104
    105
    14
    106
    Units: percent change
        least squares mean (standard error)
    -63.0 ( 1.70 )
    -68.8 ( 1.61 )
    -66.9 ( 3.75 )
    2.1 ( 1.67 )
    Statistical analysis title
    		 ISIS 696844 40 mg vs Pooled Placebo
    Statistical analysis description
    ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomised, baseline GA area, rate of change in GA area during Screening, and baseline plasma FB level as covariates.
    Comparison groups
    ISIS 696844 40 mg v Pooled Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -65.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -68.8
         upper limit
    		 -61.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.87
    Statistical analysis title
    		 ISIS 696844 100 mg vs Pooled Placebo
    Statistical analysis description
    ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomised, baseline GA area, rate of change in GA area during Screening, and baseline plasma FB level as covariates.
    Comparison groups
    ISIS 696844 100 mg v Pooled Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -77.3
         upper limit
    		 -60.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.19
    Statistical analysis title
    		 ISIS 696844 70 mg vs Pooled Placebo
    Statistical analysis description
    ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomised, baseline GA area, rate of change in GA area during Screening, and baseline plasma FB level as covariates.
    Comparison groups
    ISIS 696844 70 mg v Pooled Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -70.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -74.5
         upper limit
    		 -67.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.84

    Secondary: Percent Change From Baseline in Levels of Serum Complement Alternative Pathway Function (AH50) Activity at Steady State

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    End point title
    		 Percent Change From Baseline in Levels of Serum Complement Alternative Pathway Function (AH50) Activity at Steady State
    End point description
    ITT population included all subjects who were randomized and received at least one dose of the study drug. Baseline was defined as the average of Week -2 (Screening Period 2) and Week 1 (Day 1 pre-dose) assessments. Steady-state levels of complement factors or complement activity were defined as the average of available data from Week 33 to Week 49 assessments. As pre-specified, for purposes of analyses, data for placebo subjects were pooled for comparison to ISIS 696844-treated subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    		 ISIS 696844 40 mg ISIS 696844 70 mg ISIS 696844 100 mg Pooled Placebo
    Number of subjects analysed
    104
    105
    14
    106
    Units: percent change
        least squares mean (standard error)
    -22.4 ( 2.03 )
    -33.7 ( 1.93 )
    -34.2 ( 4.46 )
    -1.3 ( 1.98 )
    Statistical analysis title
    		 ISIS 696844 40 mg vs Pooled Placebo
    Statistical analysis description
    ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomized, baseline GA area, rate of change in GA area during Screening, and baseline AH50 level as covariates.
    Comparison groups
    ISIS 696844 40 mg v Pooled Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -21.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.5
         upper limit
    		 -16.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.23
    Statistical analysis title
    		 ISIS 696844 70 mg vs Pooled Placebo
    Statistical analysis description
    ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomized, baseline GA area, rate of change in GA area during Screening, and baseline AH50 level as covariates.
    Comparison groups
    ISIS 696844 70 mg v Pooled Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -32.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.8
         upper limit
    		 -28.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.19
    Statistical analysis title
    		 ISIS 696844 100 mg vs Pooled Placebo
    Statistical analysis description
    ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomized, baseline GA area, rate of change in GA area during Screening, and baseline AH50 level as covariates.
    Comparison groups
    ISIS 696844 100 mg v Pooled Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.8
         upper limit
    		 -23.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.98
    Notes
    [1] - ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomised, baseline GA area, rate of change in GA area during Screening, and baseline plasma FB level as covariates.

    Secondary: Absolute Change From Baseline in Low Luminance Visual Acuity (LLVA) - Study Eye

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    End point title
    		 Absolute Change From Baseline in Low Luminance Visual Acuity (LLVA) - Study Eye
    End point description
    Visual function assessments included LLVA assessment in study eye only. LLVA was measured on Early Treatment of Diabetic Retinopathy Study (ETDRS) chart and a 2.0 log unit neutral density filter at a starting distance of 4 meters (performed prior to dilating eyes). The letter score ranges from 0 (worse score) to 100 (best score), and a gain in LLVA from baseline indicates an improvement in visual acuity. The Markov Chain Monte Carlo (MCMC) method was used to impute missing LLVA score by treatment group based on following variable list for imputations: baseline, week 25 and week 49 LLVA scores, Stage of subjects randomized, status of exudative CNV in the fellow eye (Absence vs Presence), baseline GA area & rate of change in GA area during Screening. ITT population included all subjects who were randomized & received at least one dose of the study drug. As pre-specified, for purposes of analyses, data for placebo subjects were pooled for comparison to ISIS 696844-treated subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    		 ISIS 696844 40 mg ISIS 696844 70 mg ISIS 696844 100 mg Pooled Placebo
    Number of subjects analysed
    104
    105
    14
    106
    Units: score on a scale
        least squares mean (standard error)
    -2.1 ( 1.38 )
    -1.9 ( 1.32 )
    2.6 ( 3.02 )
    -3.1 ( 1.36 )
    Statistical analysis title
    		 ISIS 696844 40 mg vs Pooled Placebo
    Statistical analysis description
    ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomized, baseline GA area, rate of change in GA area during Screening, and baseline LLVA score as covariates.
    Comparison groups
    ISIS 696844 40 mg v Pooled Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.53
    Statistical analysis title
    		 ISIS 696844 70 mg vs Pooled Placebo
    Statistical analysis description
    ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomized, baseline GA area, rate of change in GA area during Screening, and baseline LLVA score as covariates.
    Comparison groups
    ISIS 696844 70 mg v Pooled Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.421 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 4.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.51
    Notes
    [2] - ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomized, baseline GA area, rate of change in GA area during Screening, and baseline LLVA score as covariates.
    Statistical analysis title
    		 ISIS 696844 100 mg vs Pooled Placebo
    Statistical analysis description
    ANCOVA model with treatment group and status of exudative CNV in the fellow eye (Absence vs Presence), stage of subjects randomized, baseline GA area, rate of change in GA area during Screening, and baseline LLVA score as covariates.
    Comparison groups
    ISIS 696844 100 mg v Pooled Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.098
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 12.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 57 (treatment period up to Week 45, safety follow-up period up to Week 57)
    Adverse event reporting additional description
    Safety population included all subjects who were randomised and received at least one dose of the study drug. As pre-specified, for purposes of analyses, data for placebo subjects were pooled for comparison to ISIS 696844-treated subjects.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    ISIS 696844 40 mg
    Reporting group description
    		 Subjects received a loading dose of ISIS 696844, 40 mg, SC at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose Q4W up to Week 45.

    Reporting group title
    ISIS 696844 70 mg
    Reporting group description
    		 Subjects received a loading dose of ISIS 696844, 70 mg, SC at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose, Q4W up to Week 45.

    Reporting group title
    ISIS 696844 100 mg
    Reporting group description
    		 Subjects received a loading dose of ISIS 696844, 100 mg, SC at Weeks 1, 3, and 5 (on Days 1, 15, and 29), followed by 1 dose, Q4W up to Week 45.

    Reporting group title
    Pooled Placebo
    Reporting group description
    		 Subjects received matching placebo, either 40 mg, 70 mg, or 100 mg, SC at Weeks 1,3 and 5 (on Days 1, 15, and 29), followed by 1 dose, Q4W up to Week 45.

    Serious adverse events
    		 ISIS 696844 40 mg ISIS 696844 70 mg ISIS 696844 100 mg Pooled Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 104 (17.31%)
    12 / 105 (11.43%)
    1 / 14 (7.14%)
    16 / 106 (15.09%)
         number of deaths (all causes)
    1
    0
    0
    1
         number of deaths resulting from adverse events
    1
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian cancer
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign uterine neoplasm
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Vascular graft thrombosis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative respiratory failure
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    2 / 104 (1.92%)
    2 / 105 (1.90%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    2 / 106 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Normocytic anaemia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis microscopic
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ISIS 696844 40 mg ISIS 696844 70 mg ISIS 696844 100 mg Pooled Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 104 (71.15%)
    71 / 105 (67.62%)
    13 / 14 (92.86%)
    70 / 106 (66.04%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 104 (1.92%)
    2 / 105 (1.90%)
    2 / 14 (14.29%)
    1 / 106 (0.94%)
         occurrences all number
    4
    2
    2
    1
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Extravasation
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Genital rash
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Cough
         subjects affected / exposed
    4 / 104 (3.85%)
    6 / 105 (5.71%)
    0 / 14 (0.00%)
    5 / 106 (4.72%)
         occurrences all number
    5
    6
    0
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Depression
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    1
    1
    1
    2
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    8 / 104 (7.69%)
    3 / 105 (2.86%)
    0 / 14 (0.00%)
    3 / 106 (2.83%)
         occurrences all number
    10
    4
    0
    3
    White blood cells urine positive
         subjects affected / exposed
    3 / 104 (2.88%)
    3 / 105 (2.86%)
    1 / 14 (7.14%)
    3 / 106 (2.83%)
         occurrences all number
    3
    3
    1
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    4 / 104 (3.85%)
    3 / 105 (2.86%)
    3 / 14 (21.43%)
    4 / 106 (3.77%)
         occurrences all number
    4
    3
    3
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 104 (0.00%)
    3 / 105 (2.86%)
    2 / 14 (14.29%)
    1 / 106 (0.94%)
         occurrences all number
    0
    6
    3
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 104 (0.00%)
    3 / 105 (2.86%)
    2 / 14 (14.29%)
    2 / 106 (1.89%)
         occurrences all number
    0
    3
    2
    2
    Platelet count decreased
         subjects affected / exposed
    5 / 104 (4.81%)
    2 / 105 (1.90%)
    2 / 14 (14.29%)
    4 / 106 (3.77%)
         occurrences all number
    10
    2
    2
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 104 (0.96%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    5 / 106 (4.72%)
         occurrences all number
    1
    2
    2
    7
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Red blood cells urine positive
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    2
    0
    2
    2
    Transaminases increased
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urinary sediment present
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    0
    1
    1
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 104 (0.96%)
    7 / 105 (6.67%)
    2 / 14 (14.29%)
    0 / 106 (0.00%)
         occurrences all number
    1
    7
    3
    0
    Injury, poisoning and procedural complications
    Skin laceration
         subjects affected / exposed
    1 / 104 (0.96%)
    3 / 105 (2.86%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    1
    4
    1
    2
    Ligament sprain
         subjects affected / exposed
    2 / 104 (1.92%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    2
    2
    1
    0
    Head injury
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    6 / 104 (5.77%)
    4 / 105 (3.81%)
    1 / 14 (7.14%)
    5 / 106 (4.72%)
         occurrences all number
    6
    5
    1
    5
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    4 / 104 (3.85%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    3 / 106 (2.83%)
         occurrences all number
    4
    1
    1
    3
    Bundle branch block right
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 104 (3.85%)
    6 / 105 (5.71%)
    0 / 14 (0.00%)
    5 / 106 (4.72%)
         occurrences all number
    4
    8
    0
    5
    Sciatica
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 105 (0.95%)
    2 / 14 (14.29%)
    0 / 106 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Dizziness
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    3 / 106 (2.83%)
         occurrences all number
    0
    0
    1
    3
    Eye disorders
    SE or FE: Visual acuity reduced
         subjects affected / exposed
    7 / 104 (6.73%)
    5 / 105 (4.76%)
    0 / 14 (0.00%)
    7 / 106 (6.60%)
         occurrences all number
    7
    5
    0
    8
    Study Eye (SE) or Fellow Eye (FE): Dry age-related macular degeneration
         subjects affected / exposed
    11 / 104 (10.58%)
    4 / 105 (3.81%)
    1 / 14 (7.14%)
    10 / 106 (9.43%)
         occurrences all number
    14
    4
    1
    10
    SE or FE: Choroidal neovascularisation
         subjects affected / exposed
    4 / 104 (3.85%)
    6 / 105 (5.71%)
    1 / 14 (7.14%)
    6 / 106 (5.66%)
         occurrences all number
    4
    6
    1
    6
    SE or FE: Posterior capsule opacification
         subjects affected / exposed
    3 / 104 (2.88%)
    6 / 105 (5.71%)
    1 / 14 (7.14%)
    3 / 106 (2.83%)
         occurrences all number
    6
    6
    2
    4
    SE or FE: Detachment of retinal pigment epithelium
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    SE or FE: Conjunctivitis allergic
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    SE or FE: Epiretinal membrane
         subjects affected / exposed
    3 / 104 (2.88%)
    3 / 105 (2.86%)
    2 / 14 (14.29%)
    2 / 106 (1.89%)
         occurrences all number
    3
    3
    2
    3
    SE or FE: Vitreous detachment
         subjects affected / exposed
    6 / 104 (5.77%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    1 / 106 (0.94%)
         occurrences all number
    6
    2
    1
    1
    SE or FE: Visual impairment
         subjects affected / exposed
    5 / 104 (4.81%)
    5 / 105 (4.76%)
    2 / 14 (14.29%)
    5 / 106 (4.72%)
         occurrences all number
    6
    5
    2
    5
    SE or FE: Dry eye
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    1
    1
    1
    0
    SE or FE: Retinal pigmentation
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    SE or FE: Retinal oedema
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    1 / 106 (0.94%)
         occurrences all number
    3
    0
    1
    1
    SE or FE: Retinal haemorrhage
         subjects affected / exposed
    5 / 104 (4.81%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    5
    2
    1
    2
    SE or FE: Retinal cyst
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    2
    1
    0
    SE or FE: Subretinal fluid
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    1
    0
    2
    0
    SE or FE: Subretinal hyperreflective exudation
         subjects affected / exposed
    0 / 104 (0.00%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    2
    2
    0
    SE or FE: Vitreous floaters
         subjects affected / exposed
    2 / 104 (1.92%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    2
    3
    1
    0
    SE only: Dry age-related macular degeneration
         subjects affected / exposed
    7 / 104 (6.73%)
    1 / 105 (0.95%)
    0 / 14 (0.00%)
    5 / 106 (4.72%)
         occurrences all number
    8
    1
    0
    5
    SE only: Choroidal neovascularisation
         subjects affected / exposed
    2 / 104 (1.92%)
    3 / 105 (2.86%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    2
    3
    1
    2
    SE only: Posterior capsule opacification
         subjects affected / exposed
    3 / 104 (2.88%)
    3 / 105 (2.86%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    3
    3
    1
    2
    SE only: Subretinal hyperreflective exudation
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    SE only: Vitreous detachment
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    1 / 106 (0.94%)
         occurrences all number
    1
    0
    1
    1
    SE only: Epiretinal membrane
         subjects affected / exposed
    0 / 104 (0.00%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    0
    2
    1
    2
    SE only: Subretinal fluid
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    SE only: Retinal pigmentation
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    SE only: Retinal haemorrhage
         subjects affected / exposed
    4 / 104 (3.85%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    4
    1
    1
    0
    SE only: Retinal cyst
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    1
    0
    SE only: Visual impairment
         subjects affected / exposed
    3 / 104 (2.88%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    1 / 106 (0.94%)
         occurrences all number
    3
    2
    1
    1
    SE only: Vitreous floaters
         subjects affected / exposed
    1 / 104 (0.96%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    1
    2
    1
    0
    FE only: Dry age-related macular degeneration
         subjects affected / exposed
    5 / 104 (4.81%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    3 / 106 (2.83%)
         occurrences all number
    5
    1
    1
    3
    FE only: Posterior capsule opacification
         subjects affected / exposed
    3 / 104 (2.88%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    3
    2
    1
    2
    FE only: Visual impairment
         subjects affected / exposed
    2 / 104 (1.92%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    2
    2
    1
    2
    FE only: Epiretinal membrane
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    1 / 106 (0.94%)
         occurrences all number
    3
    0
    1
    1
    FE only: Retinal oedema
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    1
    0
    1
    0
    FE only: Subretinal fluid
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    1
    0
    1
    0
    FE only: Subretinal hyperreflective exudation
         subjects affected / exposed
    0 / 104 (0.00%)
    2 / 105 (1.90%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Both eyes (OU): Conjunctivitis allergic
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    OU: Detachment of retinal pigment epithelium
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    OU: Dry eye
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 104 (2.88%)
    4 / 105 (3.81%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    4
    4
    1
    2
    Diarrhoea
         subjects affected / exposed
    3 / 104 (2.88%)
    4 / 105 (3.81%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    3
    4
    1
    2
    Abdominal discomfort
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    4 / 104 (3.85%)
    5 / 105 (4.76%)
    2 / 14 (14.29%)
    3 / 106 (2.83%)
         occurrences all number
    6
    5
    2
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 104 (7.69%)
    7 / 105 (6.67%)
    0 / 14 (0.00%)
    7 / 106 (6.60%)
         occurrences all number
    9
    7
    0
    7
    Back pain
         subjects affected / exposed
    5 / 104 (4.81%)
    6 / 105 (5.71%)
    0 / 14 (0.00%)
    4 / 106 (3.77%)
         occurrences all number
    5
    8
    0
    4
    Pain in extremity
         subjects affected / exposed
    2 / 104 (1.92%)
    3 / 105 (2.86%)
    1 / 14 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    2
    3
    1
    2
    Intervertebral disc compression
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fibromyalgia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    1 / 106 (0.94%)
         occurrences all number
    1
    0
    1
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    2 / 104 (1.92%)
    3 / 105 (2.86%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    2
    3
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 104 (0.96%)
    2 / 105 (1.90%)
    2 / 14 (14.29%)
    1 / 106 (0.94%)
         occurrences all number
    1
    2
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    8 / 104 (7.69%)
    5 / 105 (4.76%)
    0 / 14 (0.00%)
    12 / 106 (11.32%)
         occurrences all number
    9
    5
    0
    15
    Urinary tract infection
         subjects affected / exposed
    13 / 104 (12.50%)
    7 / 105 (6.67%)
    1 / 14 (7.14%)
    11 / 106 (10.38%)
         occurrences all number
    15
    11
    1
    13
    COVID-19
         subjects affected / exposed
    14 / 104 (13.46%)
    15 / 105 (14.29%)
    1 / 14 (7.14%)
    16 / 106 (15.09%)
         occurrences all number
    14
    15
    1
    16
    Onychomycosis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 105 (0.00%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    4 / 104 (3.85%)
    3 / 105 (2.86%)
    1 / 14 (7.14%)
    3 / 106 (2.83%)
         occurrences all number
    5
    5
    1
    3
    Localised infection
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 105 (0.95%)
    1 / 14 (7.14%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2020
    The following changes were made as per amendment 1: 1. Extended duration of Screening Period 1 to accommodate the need for subjects and/or sites to delay randomisation for a variety of reasons, including COVID-19 exposure 2. Updated the description of repeating procedures and calculation of the rate of GA area growth for stratification purposes 3. Revised inclusion and exclusion criteria
    01 Nov 2022
    The following changes were made as per amendment 2: 1. Revised inclusion and exclusion criteria 2. Added a second interim analyses for assessment of efficacy and safety endpoints when ≥50% of subjects had reached the Week 49 visit
    15 May 2023
    The following changes were made as per amendment 3: 1. Changed the primary efficacy endpoint from absolute change in GA area to rate of growth (slope) 2. Added a secondary objective and corresponding endpoint to evaluate the effect of ISIS 696844 on the absolute change in GA area measured by FAF

    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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