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    Clinical Trial Results:
    A Phase III, Multicenter, Randomised, Double-Masked, Sham-Controlled Study to assess the Efficacy and Safety of Lampalizumab Administered Intravitreally to Patients with Geographic Atrophy Secondary to Age-Related Macular Degeneration

    Summary
    EudraCT number
    		 2014-000106-35
    Trial protocol
    		 HU   DE   IT   AT   DK   GB   SE   NL   ES   BE   PT   SK   FR  
    Global end of trial date
    23 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Feb 2019
    First version publication date
    02 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GX29185
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02247531
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    23 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy of intravitreal injections of 10-mg lampalizumab administered every 4 weeks (Q4W) or every 6 weeks (Q6W) in complement factor I (CFI)-profile biomarker-positive and CFI-profile biomarker-negative subjects compared with sham control.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 553
    Country: Number of subjects enrolled
    France: 57
    Country: Number of subjects enrolled
    Germany: 55
    Country: Number of subjects enrolled
    United Kingdom: 54
    Country: Number of subjects enrolled
    Austria: 38
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Switzerland: 10
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    Slovakia: 8
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Peru: 10
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Argentina: 2
    Worldwide total number of subjects
    975
    EEA total number of subjects
    360
    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)
    53
    From 65 to 84 years
    716
    85 years and over
    206

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 975 subjects were randomised to the study at 144 study sites across 22 countries. The study was terminated early by the Sponsor due to lack of efficacy.

    Pre-assignment
    Screening details
    		 This study enrolled subjects with bilateral Geographic Atrophy (GA) secondary to Age-Related Macular Degeneration (AMD) and no signs of prior or active choroidal neovascularisation (CNV), age >= 50 years with a valid complement factor I (CFI)-profile biomarker result.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sham Comparator
    Arm description
    		 Subjects received sham comparator once every 4 weeks (Q4W) or once every 6 weeks (Q6W) starting at the Day 1 visit.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Lampalizumab Q4W
    Arm description
    		 Subjects received 10 mg (milligrams) dose of lampalizumab by intravitreal injection Q4W starting at the Day 1 visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lampalizumab
    Investigational medicinal product code
    RO5490249
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Lampalizumab was administered at a dose of 10 milligrams (mg) as an intravitreal injection Q4W starting at the Day 1 visit.

    Arm title
    		 Lampalizumab Q6W
    Arm description
    		 Subjects received 10 mg dose of lampalizumab by intravitreal injection Q6W starting at the Day 1 visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lampalizumab
    Investigational medicinal product code
    RO5490249
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Lampalizumab was administered at a dose of 10 mg as an intravitreal injection Q6W starting at the Day 1 visit.

    Number of subjects in period 1
    		Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Started
    321
    330
    324
    Completed
    215
    205
    214
    Not completed
    106
    125
    110
         Physician decision
    -
    2
    2
         Adverse Event
    3
    4
    9
         Death
    8
    9
    5
         Other
    2
    3
    4
         Non-compliance
    2
    2
    -
         Withdrawal by Subject
    26
    31
    25
         Study Terminated by Sponsor
    64
    66
    62
         Lost to follow-up
    1
    8
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sham Comparator
    Reporting group description
    		 Subjects received sham comparator once every 4 weeks (Q4W) or once every 6 weeks (Q6W) starting at the Day 1 visit.

    Reporting group title
    Lampalizumab Q4W
    Reporting group description
    		 Subjects received 10 mg (milligrams) dose of lampalizumab by intravitreal injection Q4W starting at the Day 1 visit.

    Reporting group title
    Lampalizumab Q6W
    Reporting group description
    		 Subjects received 10 mg dose of lampalizumab by intravitreal injection Q6W starting at the Day 1 visit.

    Reporting group values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W Total
    Number of subjects
    		 321 330 324 975
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 77.6 ( 8.3 ) 77.3 ( 7.8 ) 78.7 ( 8.0 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 191 197 190 578
        Male
    		 130 133 134 397
    Geographic Atrophy (GA) Area, as Assessed by Fundus Autofluoresence (FAF)
    At baseline the area of GA was assessed by FAF. Intent-to-treat (ITT) population included all the subjects who were randomised to the study. Overall number of baseline subjects for GA area in the reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 321, 330, and 324, respectively.
    Units: millimetre square (mm^2)
        arithmetic mean (standard deviation)
    		 7.554 ( 3.983 ) 8.308 ( 3.916 ) 8.498 ( 4.260 ) -
    Number of Absolute Scotomatous Points as Assessed by Mesopic Micrometry
    Scotomatous points were the testing points on microperimetry examination that were centered on the macula and reported a lack of retinal sensitivity within the range tested. Mesopic microperimetry assessments were performed post-dilation on the study eye only, and the data was forwarded to the central reading centre. Overall number of baseline subjects for number of scotomatous points in the reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 48, 58, and 55, respectively.
    Units: number of absolute scotomatous points
        arithmetic mean (standard deviation)
    		 23.2 ( 13.5 ) 28.2 ( 17.3 ) 27.9 ( 14.4 ) -
    Macular Sensitivity as Assessed by Mesopic Microperimetry
    Mesopic microperimetry was used to assess macular sensitivity and assessments were performed post-dilation on the study eye only, and the data was forwarded to the central reading centre. Overall number of baseline subjects for macular sensitivity in the reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 48, 57, and 54, respectively.
    Units: decibel (dB)
        arithmetic mean (standard deviation)
    		 6.5 ( 3.3 ) 5.7 ( 3.8 ) 5.3 ( 3.2 ) -
    Best Corrected Visual Acuity (BCVA) Score as Assessed by Early Treatment Diabetic Retinopathy Study
    BCVA score was based on number of letters read correctly on ETDRS visual acuity chart assessed at starting distance of 4 metres. BCVA score testing was performed prior to dilating the eyes. BCVA score ranges from 0 to 100 letters in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). ITT population included all the subjects who were randomised to the study. Overall number of baseline subjects for BCVA score in the reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 319, 330, and 321, respectively.
    Units: letters
        arithmetic mean (standard deviation)
    		 66.1 ( 9.8 ) 66.0 ( 9.6 ) 65.7 ( 9.8 ) -
    Low Luminance Visual Acuity (LLVA) as Assessed by ETDRS Chart Under Low Luminance Conditions
    LLVA was measured by placing a 2.0-log-unit neutral density filter over best correction for that eye and having the subjects read the normally illuminated ETDRS chart. Assessment was performed prior to dilating the eyes. The LLVA score was based on number of letters read correctly on the ETDRS visual acuity chart assessed at a starting distance of 4 m. ITT population included all the subjects who were randomised to the study. Overall number of baseline subjects for LLVA score in the reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 310, 322, and 310, respectively.
    Units: letters
        arithmetic mean (standard deviation)
    		 36.8 ( 16.5 ) 36.1 ( 17.5 ) 35.8 ( 16.8 ) -
    Binocular Reading Speed as Assessed by Minnesota Low-Vision Reading Test or Radner Reading Charts
    MNRead acuity cards were suitable for measuring reading speed of normal and low-vision subjects. Sentences that could not be read should be recorded as 0 for time and 10 for errors. Radner Reading Cards were suitable for measuring reading speed, visual acuity, and critical print size. Test stopped when reading time was longer than 20 seconds. ITT population included all subjects who were randomised to the study. Overall number of baseline subjects for binocular reading speed in the reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 298, 303, and 302, respectively.
    Units: words per minute (wpm)
        arithmetic mean (standard deviation)
    		 105.16 ( 56.94 ) 104.38 ( 54.35 ) 99.75 ( 56.56 ) -
    Monocular Maximum Reading Speed as Assessed by MNRead Charts or Radner Reading Charts
    MNRead acuity cards were suitable for measuring reading speed of normal and low-vision subjects. Sentences that could not be read should be recorded as 0 for time and 10 for errors. Radner Reading Cards were suitable for measuring reading speed, visual acuity, and critical print size. Test stopped when reading time was longer than 20 seconds. ITT population included all subjects who were randomised to the study. Overall number of baseline subjects for monocular reading speed in the reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 300, 310, and 304, respectively.
    Units: wpm
        arithmetic mean (standard deviation)
    		 81.20 ( 57.48 ) 80.38 ( 53.70 ) 74.52 ( 50.11 ) -
    National Eye Institute Visual Functioning Questionnaire 25-item (NEI VFQ-25) Version Composite Score
    It included 25 items based on which overall composite VFQ score and 12 subscales (general vision,near vision,distance vision,ocular pain,social functioning,mental health,roll difficulties,dependency,driving,color vision and peripheral vision) were derived. For each subscale and total score, score range is 0 to 100, higher score represents better functioning. ITT population included all subjects who were randomised to study. Overall number of baseline subjects for NEI-VFQ-25 score in reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 283, 299, and 296, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 64.84 ( 15.80 ) 62.88 ( 17.50 ) 64.03 ( 17.65 ) -
    NEI VFQ-25 Near Activity Subscale Score
    NEI-VFQ-25 questionnaire included 25 items based on which near activities were measured. Near activities are defined as reading ordinary print in newspapers, performing work requiring near vision, or finding something on crowded shelf. Response to each question converted to 0-100 score. Higher score represents better functioning. ITT population included all subjects who were randomised to study. Overall number of baseline subjects for NEI VFQ-25 near activity subscale score in the reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 283, 299, and 296, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 53.89 ( 19.91 ) 51.68 ( 21.92 ) 53.24 ( 22.07 ) -
    NEI VFQ-25 Distance Activity Subscale Score
    NEI-VFQ-25 questionnaire included 25 items based on which distance activities was measured. Distance activities are defined as reading street signs or names on stores, and going down stairs, steps, or curbs. Response to each question converted to 0-100 score. A higher score represents better functioning. ITT population included all subjects who were randomised to the study. Overall number of baseline subjects for NEI VFQ-25 distance activity subscale score in the reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 283, 299, and 296, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 62.68 ( 21.41 ) 58.57 ( 22.03 ) 60.95 ( 21.55 ) -
    Mean Functional Reading Independence (FRI) Index
    FRI was an interviewer-administered questionnaire with 7 items on functional reading activities most relevant to GA AMD subjects. It has one total index score. For each reading activity performed in the past 7 days, subjects were asked about the extent to which they required vision aids, adjustments in activity, or help from another subject. ITT population included all subjects who were randomised to the study. Overall number of baseline subjects for FRI index in the reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 278, 296, and 293, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 2.70 ( 0.79 ) 2.66 ( 0.82 ) 2.64 ( 0.87 ) -
    GA Area in Complement Factor I (CFI) Positive Subjects
    For CFI profile, positive biomarker status refers to the presence of the risk allele at CFI and at least one risk allele at CFH or risk locus containing both C2/CFB. ITT population included all subjects who were randomised to study. Overall number of baseline CFI positive subjects for GA area in reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 194, 199, and 194, respectively.
    Units: mm^2
        arithmetic mean (standard deviation)
    		 7.491 ( 4.068 ) 8.183 ( 3.835 ) 8.652 ( 4.250 ) -
    GA Area in CFI Negative Subjects
    For CFI profile, negative biomarker status refers to the absence of the risk allele at CFI and at least one risk allele at CFH or risk locus containing both C2/CFB. ITT population included all subjects who were randomized to study. Overall number of baseline CFI negative subjects for GA area in reporting groups; Sham Comparator, Lampalizumab Q4W, and Lampalizumab Q6W were 127, 131, and 130, respectively.
    Units: mm^2
        arithmetic mean (standard deviation)
    		 7.650 ( 3.862 ) 8.499 ( 4.044 ) 8.268 ( 4.281 ) -

    End points

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    End points reporting groups
    Reporting group title
    Sham Comparator
    Reporting group description
    		 Subjects received sham comparator once every 4 weeks (Q4W) or once every 6 weeks (Q6W) starting at the Day 1 visit.

    Reporting group title
    Lampalizumab Q4W
    Reporting group description
    		 Subjects received 10 mg (milligrams) dose of lampalizumab by intravitreal injection Q4W starting at the Day 1 visit.

    Reporting group title
    Lampalizumab Q6W
    Reporting group description
    		 Subjects received 10 mg dose of lampalizumab by intravitreal injection Q6W starting at the Day 1 visit.

    Primary: Change From Baseline in Geographic Atropy (GA) Area, as Assessed by Fundus Autofluoresence (FAF) at Week 48

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    End point title
    		 Change From Baseline in Geographic Atropy (GA) Area, as Assessed by Fundus Autofluoresence (FAF) at Week 48
    End point description
    The change in GA lesion area was measured by FAF and analysis of FAF images was performed by the central reading centre. A positive change from baseline indicates an increase in size of GA lesion area (worsening; disease progression). The intent-to-treat (ITT) population included all the subjects who were randomised to the study. Subjects analysed in this endpoint were those included in mixed-effect model repeated measures (MMRM) analysis.
    End point type
    Primary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    291
    293
    291
    Units: millimetre square (mm^2)
        arithmetic mean (standard error)
    1.932 ( 0.056 )
    2.089 ( 0.056 )
    2.019 ( 0.056 )
    Statistical analysis title
    		 Lampalizumab Q4W vs Sham Comaparator
    Statistical analysis description
    Week 48: MMRM analysis uses change as response variable and included treatment group, visit, treatment−by−visit interaction, baseline GA area, lesion location, contiguity, biomarker status, modified baseline BCVA and sex.
    Comparison groups
    Lampalizumab Q4W v Sham Comparator
    Number of subjects included in analysis
    584
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0479
    Method
    		 MMRM
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    0.157
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 0.313
    Statistical analysis title
    		 Lampalizumab Q6W vs Sham Comparator
    Statistical analysis description
    Week 48: MMRM analysis uses change as response variable and included treatment group, visit, treatment−by−visit interaction, baseline GA area, lesion location, contiguity, biomarker status, modified baseline BCVA and sex.
    Comparison groups
    Sham Comparator v Lampalizumab Q6W
    Number of subjects included in analysis
    582
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2739
    Method
    		 MMRM
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    0.087
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.069
         upper limit
    		 0.243

    Primary: Change From Baseline in GA Area in Complement Factor I (CFI) Positive and Negative Subjects at Week 48

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    End point title
    		 Change From Baseline in GA Area in Complement Factor I (CFI) Positive and Negative Subjects at Week 48
    End point description
    For CFI profile, positive or negative biomarker status refers to the presence (carrier) or absence of the risk allele at CFI and at least one risk allele at complement factor H (CFH) or risk locus containing both complement component 2 and complement factor B (C2/CFB). The change in GA lesion area was measured by FAF and analysis of FAF images was performed by the central reading centre. A positive change from baseline indicates an increase in size of GA lesion area (worsening; disease progression). ITT population included all the subjects who were randomised to the study. Reported here are data for CFI-positive and CFI-negative subjects within the ITT population. Here, "n" is the number of subjects who were analysed for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    321
    330
    324
    Units: mm^2
    arithmetic mean (standard error)
        CFI-Positive Subjects (n=176, 183, 172)
    2.007 ( 0.074 )
    2.057 ( 0.072 )
    2.032 ( 0.073 )
        CFI-Negative Subjects (n=115, 110, 119)
    1.809 ( 0.087 )
    2.149 ( 0.087 )
    1.991 ( 0.085 )
    Statistical analysis title
    		 Lampalizumab Q4W vs Sham Comparator
    Statistical analysis description
    CFI Positive: MMRM analysis uses change as response variable and included treatment group, visit, treatment−by−visit interaction, baseline GA area, lesion location, contiguity, biomarker status, modified baseline BCVA and sex.
    Comparison groups
    Sham Comparator v Lampalizumab Q4W
    Number of subjects included in analysis
    651
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6333
    Method
    		 MMRM
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    0.049
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.153
         upper limit
    		 0.252
    Statistical analysis title
    		 Lampalizumab Q6W vs Sham Comparator
    Statistical analysis description
    CFI Positive: MMRM analysis uses change as response variable and included treatment group, visit, treatment−by−visit interaction, baseline GA area, lesion location, contiguity, biomarker status, modified baseline BCVA and sex.
    Comparison groups
    Sham Comparator v Lampalizumab Q6W
    Number of subjects included in analysis
    645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8105
    Method
    		 MMRM
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    0.025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.23
    Statistical analysis title
    		 Lampalizumab Q4W vs Sham Comparator
    Statistical analysis description
    CFI Negative: MMRM analysis uses change as response variable and included treatment group, visit, treatment−by−visit interaction, baseline GA area, lesion location, contiguity, biomarker status, modified baseline BCVA and sex.
    Comparison groups
    Sham Comparator v Lampalizumab Q4W
    Number of subjects included in analysis
    651
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0063
    Method
    		 MMRM
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.097
         upper limit
    		 0.584
    Statistical analysis title
    		 Lampalizumab Q6W vs Sham Comparator
    Statistical analysis description
    CFI Negative: MMRM analysis uses change as response variable and included treatment group, visit, treatment−by−visit interaction, baseline GA area, lesion location, contiguity, biomarker status, modified baseline BCVA and sex.
    Comparison groups
    Sham Comparator v Lampalizumab Q6W
    Number of subjects included in analysis
    645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1359
    Method
    		 MMRM
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    0.182
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.058
         upper limit
    		 0.422

    Secondary: Change From Baseline in Number of Absolute Scotomatous Points Assessed by Mesopic Microperimetry at Week 48

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    End point title
    		 Change From Baseline in Number of Absolute Scotomatous Points Assessed by Mesopic Microperimetry at Week 48
    End point description
    Scotomatous points were the testing points on microperimetry examination that were centered on the macula and reported a lack of retinal sensitivity within the range tested. Mesopic microperimetry assessments were performed post-dilation on the study eye only, and the data was forwarded to the central reading centre. A positive change from baseline indicates an increase in the number of absolute scotomatous points (more lack of retinal sensitivity); disease worsening. The microperimetry analysis population consisted of all subjects who met the microperimetry eligibility criteria assessed by the reading centre (subjects at selected sites only; subjects grouped according to treatment assigned at randomisation). Subjects analysed in this end point were those included in MMRM analysis. The data was collected up to Week 48 instead of Week 96, due to early termination of the study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    39
    42
    43
    Units: number of absolute scotomatous points
        arithmetic mean (standard error)
    5.4 ( 1.6 )
    5.0 ( 1.5 )
    6.7 ( 1.5 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Macular Sensitivity as Assessed by Mesopic Microperimetry at Week 48

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    End point title
    		 Change From Baseline in Macular Sensitivity as Assessed by Mesopic Microperimetry at Week 48
    End point description
    Mesopic microperimetry was used to assess macular sensitivity and assessments were performed post-dilation on the study eye only, and the data was forwarded to the central reading center. A negative change from baseline indicates a decrease in the mean macular sensitivity; disease worsening. Data were collected up to Week 48 instead of Week 96, due to early termination of the study. ITT population included all the subjects who were randomised to the study. Subjects analysed in this endpoint were those included in the MMRM analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    39
    41
    42
    Units: decibel (dB)
        arithmetic mean (standard error)
    -0.99 ( 0.36 )
    -0.89 ( 0.34 )
    -1.25 ( 0.35 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Best Corrected Visual Acuity (BCVA) Score as Assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) Chart at Week 48

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    End point title
    		 Change From Baseline in Best Corrected Visual Acuity (BCVA) Score as Assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) Chart at Week 48
    End point description
    BCVA score was based on the number of letters read correctly on the ETDRS visual acuity chart assessed at a starting distance of 4 metres (m). A decrease in the VA score indicates a worsening of visual acuity. BCVA score testing was performed prior to dilating the eyes. BCVA score ranges from 0 to 100 letters in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). A negative change from baseline indicates a decrease in the visual acuity; disease worsening. ITT population included all the subjects who were randomized to the study. Subjects analysed in this end point were those included in MMRM analysis. The data was collected up to Week 48 instead of Week 96, due to early termination of the study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    288
    286
    287
    Units: letters
        arithmetic mean (standard error)
    -5.3 ( 0.7 )
    -4.6 ( 0.7 )
    -5.1 ( 0.7 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Less Than 15 Letters Loss From Baseline in BCVA Score at Week 48

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    End point title
    		 Percentage of Subjects with Less Than 15 Letters Loss From Baseline in BCVA Score at Week 48
    End point description
    Loss of less than 15 letters from baseline was assessed by the ETDRS chart at a starting distance of 4 m. BCVA was measured using an eye chart and was reported as the number of letters read correctly (ranging from 0 to 100 letters). The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). ITT population included all the subjects who were randomized to the study. The data was collected up to Week 48 instead of Week 96, due to early termination of the study.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    288
    286
    287
    Units: percentage of subjects
        number (confidence interval 95%)
    86.8 (82.9 to 90.7)
    87.8 (84.0 to 91.6)
    86.4 (82.4 to 90.4)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Low Luminance Visual Acuity (LLVA) as Assessed by ETDRS Chart Under Low Luminance Conditions at Week 48

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    End point title
    		 Change From Baseline in Low Luminance Visual Acuity (LLVA) as Assessed by ETDRS Chart Under Low Luminance Conditions at Week 48
    End point description
    The LLVA was measured by placing a 2.0-log-unit neutral density filter over the best correction for that eye and having the subject read the normally illuminated ETDRS chart. The assessment was performed prior to dilating the eyes. A negative change from baseline indicates a decrease in the visual acuity; disease worsening. Data were collected up to Week 48 instead of Week 96, due to early termination of the study. ITT population included all the subjects who were randomised to the study. Subjects analysed in this endpoint were those included in the MMRM analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    274
    278
    274
    Units: letters
        arithmetic mean (standard error)
    -2.5 ( 0.6 )
    -2.6 ( 0.6 )
    -3.6 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Less Than 15 Letters Loss From Baseline in LLVA Score at Week 48

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    End point title
    		 Percentage of Subjects with Less Than 15 Letters Loss From Baseline in LLVA Score at Week 48
    End point description
    Loss of less than 15 letters from baseline was assessed by the ETDRS chart at a starting distance of 4 m. Data were collected up to Week 48 instead of Week 96, due to early termination of the study. ITT population included all the subjects who were randomised to the study.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    274
    278
    274
    Units: percentage of subjects
        number (confidence interval 95%)
    87.6 (83.7 to 91.5)
    89.9 (86.4 to 93.5)
    86.9 (82.9 to 90.9)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Binocular Reading Speed as Assessed by Minnesota Low-Vision Reading Test (MNRead) Charts or Radner Reading Charts at Week 48

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    End point title
    		 Change From Baseline in Binocular Reading Speed as Assessed by Minnesota Low-Vision Reading Test (MNRead) Charts or Radner Reading Charts at Week 48
    End point description
    MNRead acuity cards were continuous-text reading-acuity cards suitable for measuring the reading acuity and reading speed of normal and low-vision subjects. The MNRead acuity cards consisted of single, simple sentences with equal numbers of characters. A stopwatch was used to record time to a tenth of a second. Sentences that could not be read or were not attempted due to vision should be recorded as 0 for time and 10 for errors. The Radner Reading Cards were suitable for measuring reading speed, reading visual acuity, and critical print size. The reading test was stopped when the reading time was longer than 20 seconds or when the subject was making severe errors. A negative change from baseline indicates a decrease in the binocular reading speed; disease worsening. Reported here is the ITT population included in MMRM analysis. The data was collected up to Week 48 instead of Week 96, due to early termination of the study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    261
    255
    266
    Units: words per minute (wpm)
        arithmetic mean (standard error)
    -15.27 ( 2.33 )
    -13.92 ( 2.36 )
    -14.20 ( 2.31 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Monocular Maximum Reading Speed as Assessed by MNRead Charts or Radner Reading Charts at Week 48

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    End point title
    		 Change From Baseline in Monocular Maximum Reading Speed as Assessed by MNRead Charts or Radner Reading Charts at Week 48
    End point description
    MNRead acuity cards were continuous-text reading-acuity cards suitable for measuring reading acuity and reading speed of normal and low-vision participants. A stopwatch was used to record time to a tenth of a second. Sentences that could not be read or were not attempted due to vision should be recorded as 0 for time and 10 for errors. Radner Reading Cards were suitable for measuring reading speed, reading visual acuity, and critical print size. Reading test was stopped when reading time was longer than 20 seconds or when participant was making severe errors. A negative change from baseline indicates a decrease in the monocular reading speed; disease worsening. The data was collected up to Week 48 instead of Week 96, due to early termination of the study. ITT population included all the subjects who were randomised to the study. Subjects analysed in this endpoint were those included in the MMRM analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    264
    264
    272
    Units: wpm
        arithmetic mean (standard error)
    -16.58 ( 2.30 )
    -16.46 ( 2.30 )
    -18.30 ( 2.27 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in National Eye Institute Visual Functioning Questionnaire 25-item (NEI VFQ-25) Version Composite Score at Week 48

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    End point title
    		 Change From Baseline in National Eye Institute Visual Functioning Questionnaire 25-item (NEI VFQ-25) Version Composite Score at Week 48
    End point description
    NEI-VFQ-25 questionnaire included 25 items based on which overall composite VFQ score and 12 subscales were derived: near activities, distance activities, general health, general vision, ocular pain, vision−specific social functioning, vision−specific mental health, vision−specific role difficulties, vision−specific dependency, driving, color vision and peripheral vision. Response to each question converted to 0-100 score. Each subscale or total score is the average of items contributing to the score. For each subscale and total score the score range is 0 to 100 with a higher score representing better functioning. A negative change from baseline indicates a decrease in the visual functioning; disease worsening. Data were collected up to Week 48 instead of Week 96, due to early termination of the study. ITT population included all the subjects who were randomised to the study. Subjects analysed in this endpoint were those included in the MMRM analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    251
    259
    265
    Units: score on a scale
        arithmetic mean (standard error)
    -2.08 ( 0.74 )
    -0.86 ( 0.73 )
    -1.05 ( 0.72 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in NEI VFQ-25 Near Activity Subscale Score at Week 48

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    End point title
    		 Change from Baseline in NEI VFQ-25 Near Activity Subscale Score at Week 48
    End point description
    NEI-VFQ-25 questionnaire included 25 items based on which near activities were measured. Near activities are defined as reading ordinary print in newspapers, performing work or hobbies requiring near vision, or finding something on a crowded shelf. Response to each question converted to 0-100 score. A higher score represents better functioning. A negative change from baseline indicates a decrease in the near visual activities; disease worsening. ITT population included all the subjects who were randomized to the study. Subjects analysed in this end point were those included in MMRM analysis. The data was collected up to Week 48 instead of Week 96, due to early termination of the study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    251
    259
    265
    Units: score on a scale
        arithmetic mean (standard error)
    -4.12 ( 0.91 )
    -1.49 ( 0.89 )
    -1.93 ( 0.88 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in NEI VFQ-25 Distance Activity Subscale Score at Week 48

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    End point title
    		 Change from Baseline in NEI VFQ-25 Distance Activity Subscale Score at Week 48
    End point description
    NEI-VFQ-25 questionnaire included 25 items based on which distance activities were measured. Distance activities are defined as reading street signs or names on stores, and going down stairs, steps, or curbs. Response to each question converted to 0-100 score. A higher score represents better functioning. A negative change from baseline indicates a decrease in the distance visual activities; disease worsening. ITT population included all the subjects who were randomized to the study. Subjects analysed in this end point were those included in MMRM analysis. The data was collected up to Week 48 instead of Week 96, due to early termination of the study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    251
    259
    265
    Units: score on a scale
        arithmetic mean (standard error)
    -2.83 ( 1.04 )
    -1.80 ( 1.03 )
    -2.24 ( 1.01 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Functional Reading Independence (FRI) Index at Week 48

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    End point title
    		 Change From Baseline in Mean Functional Reading Independence (FRI) Index at Week 48
    End point description
    The FRI was an interviewer-administered questionnaire with 7 items on functional reading activities most relevant to GA AMD subjects. It has one total index score. The index score is an ordinal scale with higher levels representing higher FRI. For each FRI Index reading activity performed in the past 7 days, subjects were asked about the extent to which they required vision aids, adjustments in the activity, or help from another subject. A negative change from baseline indicates a decrease in the FRI; disease worsening. ITT population included all the subjects who were randomized to the study. Subjects analysed in this end point were those included in MMRM analysis. The data was collected up to Week 48 instead of Week 96, due to early termination of the study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Sham Comparator Lampalizumab Q4W Lampalizumab Q6W
    Number of subjects analysed
    248
    257
    260
    Units: score on a scale
        arithmetic mean (standard error)
    -0.16 ( 0.04 )
    -0.12 ( 0.04 )
    -0.14 ( 0.04 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 2 years
    Adverse event reporting additional description
    Safety population included all subjects who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Sham Comparator
    Reporting group description
    		 Subjects received sham comparator Q4W or Q6W starting at the Day 1 visit.

    Reporting group title
    Lampalizumab Q6W
    Reporting group description
    		 Subjects received 10 mg dose of lampalizumab by intravitreal injection Q6W starting at the Day 1 visit.

    Reporting group title
    Lampalizumab Q4W
    Reporting group description
    		 Subjects received 10 mg dose of lampalizumab by intravitreal injection Q4W starting at the Day 1 visit.

    Serious adverse events
    		 Sham Comparator Lampalizumab Q6W Lampalizumab Q4W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    99 / 318 (31.13%)
    111 / 323 (34.37%)
    113 / 329 (34.35%)
         number of deaths (all causes)
    9
    7
    10
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B−cell lymphoma
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone cancer
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma stage IV
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hepatic cancer
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal cancer stage I
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lip squamous cell carcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal cancer metastatic
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 323 (0.62%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salivary gland neoplasm
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestine carcinoma metastatic
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the vulva
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vulval cancer stage 0
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Waldenstrom’s macroglobulinaemia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 323 (0.62%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Fracture treatment
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stent-graft endoleak
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    7 / 329 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 323 (0.62%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus polyp
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio abnormal
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraocular pressure increased
         subjects affected / exposed
    1 / 318 (0.31%)
    8 / 323 (2.48%)
    10 / 329 (3.04%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 20
    7 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    2 / 318 (0.63%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    5 / 318 (1.57%)
    5 / 323 (1.55%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 318 (0.63%)
    2 / 323 (0.62%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated incisional hernia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incomplete spinal fusion
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    3 / 318 (0.94%)
    0 / 323 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain herniation
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Corneal abrasion
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 323 (0.62%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arteriovenous malformation
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 318 (0.00%)
    3 / 323 (0.93%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 318 (0.31%)
    2 / 323 (0.62%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    2 / 318 (0.63%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 318 (0.63%)
    0 / 323 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    6 / 318 (1.89%)
    2 / 323 (0.62%)
    7 / 329 (2.13%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular dissociation
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 318 (0.31%)
    2 / 323 (0.62%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    4 / 318 (1.26%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 323 (0.62%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 318 (1.26%)
    8 / 323 (2.48%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 318 (0.63%)
    2 / 323 (0.62%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve prolapse
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 323 (0.31%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Ventricular tachycardia
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery disease
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 323 (0.31%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IIIrd nerve paralysis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 323 (0.31%)
    6 / 329 (1.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoacusis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness transient
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 323 (0.62%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Choroidal neovascularisation
         subjects affected / exposed
    1 / 318 (0.31%)
    2 / 323 (0.62%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dry age−related macular degeneration
         subjects affected / exposed
    0 / 318 (0.00%)
    3 / 323 (0.93%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neovascular age−related macular degeneration
         subjects affected / exposed
    2 / 318 (0.63%)
    4 / 323 (1.24%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Open angle glaucoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic ischaemic neuropathy
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitic glaucoma
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    10 / 318 (3.14%)
    18 / 323 (5.57%)
    13 / 329 (3.95%)
         occurrences causally related to treatment / all
    0 / 14
    1 / 19
    1 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous floaters
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Posterior capsule opacification
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced transiently
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crohn’s disease
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    3 / 318 (0.94%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin necrosis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 318 (0.31%)
    2 / 323 (0.62%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cyst
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower urinary tract symptoms
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pollakiuria
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 318 (0.31%)
    2 / 323 (0.62%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Costochondritis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    4 / 318 (1.26%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 318 (0.31%)
    1 / 323 (0.31%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 318 (0.63%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 318 (0.00%)
    2 / 323 (0.62%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 318 (2.20%)
    5 / 323 (1.55%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 318 (0.94%)
    1 / 323 (0.31%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 318 (0.00%)
    3 / 323 (0.93%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal infection
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 318 (0.31%)
    2 / 323 (0.62%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 318 (0.00%)
    1 / 323 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 318 (0.00%)
    0 / 323 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 318 (0.31%)
    0 / 323 (0.00%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sham Comparator Lampalizumab Q6W Lampalizumab Q4W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    227 / 318 (71.38%)
    253 / 323 (78.33%)
    268 / 329 (81.46%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    7 / 318 (2.20%)
    39 / 323 (12.07%)
    50 / 329 (15.20%)
         occurrences all number
    14
    72
    85
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    41 / 318 (12.89%)
    28 / 323 (8.67%)
    47 / 329 (14.29%)
         occurrences all number
    50
    41
    58
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 318 (8.18%)
    22 / 323 (6.81%)
    27 / 329 (8.21%)
         occurrences all number
    26
    23
    30
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 318 (3.46%)
    9 / 323 (2.79%)
    20 / 329 (6.08%)
         occurrences all number
    11
    11
    26
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    84 / 318 (26.42%)
    97 / 323 (30.03%)
    112 / 329 (34.04%)
         occurrences all number
    205
    228
    268
    Eye pain
         subjects affected / exposed
    30 / 318 (9.43%)
    36 / 323 (11.15%)
    55 / 329 (16.72%)
         occurrences all number
    50
    93
    87
    Vitreous detachment
         subjects affected / exposed
    24 / 318 (7.55%)
    31 / 323 (9.60%)
    37 / 329 (11.25%)
         occurrences all number
    33
    41
    49
    Cataract
         subjects affected / exposed
    25 / 318 (7.86%)
    25 / 323 (7.74%)
    23 / 329 (6.99%)
         occurrences all number
    41
    36
    35
    Retinal haemorrhage
         subjects affected / exposed
    14 / 318 (4.40%)
    22 / 323 (6.81%)
    24 / 329 (7.29%)
         occurrences all number
    18
    31
    38
    Dry eye
         subjects affected / exposed
    16 / 318 (5.03%)
    16 / 323 (4.95%)
    19 / 329 (5.78%)
         occurrences all number
    26
    31
    32
    Vitreous floaters
         subjects affected / exposed
    5 / 318 (1.57%)
    26 / 323 (8.05%)
    29 / 329 (8.81%)
         occurrences all number
    8
    33
    35
    Blepharitis
         subjects affected / exposed
    11 / 318 (3.46%)
    15 / 323 (4.64%)
    26 / 329 (7.90%)
         occurrences all number
    20
    25
    55
    Vision blurred
         subjects affected / exposed
    15 / 318 (4.72%)
    12 / 323 (3.72%)
    18 / 329 (5.47%)
         occurrences all number
    24
    17
    27
    Posterior capsule opacification
         subjects affected / exposed
    11 / 318 (3.46%)
    11 / 323 (3.41%)
    20 / 329 (6.08%)
         occurrences all number
    16
    14
    26
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 318 (1.57%)
    8 / 323 (2.48%)
    18 / 329 (5.47%)
         occurrences all number
    5
    8
    20
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 318 (3.14%)
    10 / 323 (3.10%)
    26 / 329 (7.90%)
         occurrences all number
    11
    12
    26
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 318 (5.35%)
    14 / 323 (4.33%)
    22 / 329 (6.69%)
         occurrences all number
    20
    14
    22
    Arthralgia
         subjects affected / exposed
    16 / 318 (5.03%)
    14 / 323 (4.33%)
    18 / 329 (5.47%)
         occurrences all number
    20
    14
    19
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    46 / 318 (14.47%)
    36 / 323 (11.15%)
    45 / 329 (13.68%)
         occurrences all number
    65
    39
    62
    Urinary tract infection
         subjects affected / exposed
    22 / 318 (6.92%)
    14 / 323 (4.33%)
    33 / 329 (10.03%)
         occurrences all number
    34
    20
    44
    Bronchitis
         subjects affected / exposed
    16 / 318 (5.03%)
    32 / 323 (9.91%)
    25 / 329 (7.60%)
         occurrences all number
    19
    43
    29
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 318 (6.29%)
    13 / 323 (4.02%)
    19 / 329 (5.78%)
         occurrences all number
    25
    15
    20
    Influenza
         subjects affected / exposed
    13 / 318 (4.09%)
    14 / 323 (4.33%)
    23 / 329 (6.99%)
         occurrences all number
    13
    16
    28

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2014
    Protocol was amended to allow investigator site staff to perform telephone administration of the patient-reported outcome (PRO) assessments on the study subjects in countries where law and/or regulation prohibit the use of a third-party Sponsor contracted call centre to perform the telephone administration of the PRO assessments.
    04 Sep 2014
    Protocol was amended to reflect that the microperimetry assessment should be performed post-dilation.
    18 Nov 2014
    Protocol was amended to include additional inclusion/exclusion criteria to enhance subject safety and to comply with health authority requests, enabling the protocol to be conducted globally.
    06 Mar 2015
    Protocol was amended to change the telephone-based collection of patient-reported outcome questionnaires (National Eye Institute Visual Functioning Questionnaire 25-item Version and Functional Reading Independence Index) to an on-site, in-person administration format. The screening period was extended from 21 days to 28 days. To reduce the chance of user error, the sham vial appropriate handing was clarified. This amendment included small revisions and clarifications to the inclusion and exclusion criteria. The protocol expanded on use of Lucentis (at the discretion of the investigator) in either eye for any ocular condition for which it was approved in a country.
    24 Sep 2015
    Planned total sample size was updated to provide a more accurate number of planned global sites. Section Subjects included guidance regarding the procedure for handling subjects who needed an extended screening period to prevent unnecessary re-screening. In the inclusion criteria contraceptive methods for women of childbearing potential and men as well as definition of women of childbearing potential were harmonised with current international recommendations. In the exclusion criteria concurrent systemic conditions were updated to include treatment for localised in addition to systemic infection. Ongoing prophylactic use of antimicrobial therapy should be discussed with Medical Monitor. Additional details regarding the masked and unmasked roles were added. In Permitted Therapy, updated instructions were given in the event that Lucentis treatment was given at the same visit as a study eye treatment with lampalizumab/sham to help ensure subject safety. Safety Plan was updated to include transient vision loss as a potential ocular safety issue currently thought to be associated with the route of administration to help ensure subject safety. More detailed guidance was provided for the assessment of causality of adverse events. Clarified the pre-treatment procedures for subjects undergoing treatment or sham injections to help ensure subject safety. Preparation and administration of lampalizumab injection was revised to include equivalent study treatment supplies (needles) available outside of the United States and to further clarify the steps required to prepare and administer a lampalizumab injection to help ensure subject safety.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Jan 2018
    The study was terminated early by the Sponsor due to lack of efficacy of the compound.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This study was terminated early by the Sponsor. Thus, not all subjects in this study completed the full duration of treatment.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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