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    Clinical Trial Results:
    A Two-Year, Randomized, Double-Masked, Multicenter, Two-Arm Study Comparing the Efficacy and Safety of RTH258 6mg Versus Aflibercept in Subjects with Neovascular Age-Related Macular Degeneration

    Summary
    EudraCT number
    		 2014-004886-26
    Trial protocol
    		 SK   PT   FI   AT   NO   IE   ES   EE   LT   SE   DE   HU   CZ   NL   GB   LV   DK   BE   PL   GR   HR   IT  
    Global end of trial date
    08 Mar 2018

    Results information
    Results version number
    		 v1
    This version publication date
    16 Mar 2019
    First version publication date
    16 Mar 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    RTH258-C002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02434328
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alcon Research, Ltd.
    Sponsor organisation address
    6201 S. Freeway, Fort Worth, TX, United States, 76134
    Public contact
    EMEA Regulatory Affairs, Alcon Eye Care UK Ltd, eurmea.ra@alcon.com
    Scientific contact
    EMEA Regulatory Affairs, Alcon Eye Care UK Ltd, eurmea.ra@alcon.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
    08 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to compare brolucizumab (RTH258) ophthalmic solution for intravitreal (IVT) injection (6 mg) to aflibercept ophthalmic solution for IVT injection (2 mg) in subjects with untreated active choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) in the study eye. Subjects were randomized to brolucizumab 6 mg and aflibercept 2 mg in a 1:1 ratio. Subjects in both treatment arms received 3 monthly loading doses (Day 0, Week 4 and Week 8), followed by a maintenance regimen, until the end of the study. All subjects attended pre-specified visits every 4 weeks.
    Protection of trial subjects
    Prior to the start of the study, the study protocol, the informed consent and assent documents, patient instruction sheets, the Investigator’s Brochure, as well as any advertising materials used to recruit patients were submitted to institutional review boards (IRBs) and independent ethics committees (IECs). The IRB/IECs reviewed all documents and approved required documents; copies of the approval letters were provided to Alcon. Consistent with both the IRB/IEC’s requirements and all applicable regulations, the Investigators periodically provided study updates to the IRB/IEC. This study was conducted in accordance with Good Clinical Practices (GCP) and the ethical principles that have their origins in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jul 2015
    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
    Netherlands: 9
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Poland: 60
    Country: Number of subjects enrolled
    Portugal: 15
    Country: Number of subjects enrolled
    Slovakia: 46
    Country: Number of subjects enrolled
    Spain: 114
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Czech Republic: 38
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Estonia: 12
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 83
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Hungary: 84
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Italy: 42
    Country: Number of subjects enrolled
    Latvia: 12
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Switzerland: 17
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Turkey: 21
    Country: Number of subjects enrolled
    Vietnam: 9
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 28
    Worldwide total number of subjects
    739
    EEA total number of subjects
    647
    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)
    72
    From 65 to 84 years
    567
    85 years and over
    100

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from investigative sites located in Austria, Belgium, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, South Korea, Latvia, Lithuania, Netherlands, Norway, Poland, Portugal, Russia, Singapore, Slovakia, Spain, Switzerland, Taiwan, Turkey, UK, and Vietnam.

    Pre-assignment
    Screening details
    		 This reporting group includes all randomized and treated subjects (739).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brolucizumab 6 mg
    Arm description
    		 Single intravitreal (IVT) injection of brolucizumab ophthalmic solution at Day 0, Week 4, and Week 8, followed by q8w/q12w maintenance regimen until study exit
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brolucizumab ophthalmic solution
    Investigational medicinal product code
    Other name
    RTH258
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use, Ophthalmic use
    Dosage and administration details
    Brolucizumab ophthalmic solution, 6 mg/50 µL dose, administered as a single IVT injection at Day 0, Week 4, and Week 8, followed by 1 injection every 8 weeks/1 injection every 12 weeks (q8w/q12w) maintenance regimen until study exit.

    Arm title
    		 Aflibercept 2 mg
    Arm description
    		 Single IVT injection of aflibercept ophthalmic solution at Day 0, Week 4, and Week 8, followed by q8w maintenance regimen until study exit
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    EYLEA®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use, Ophthalmic use
    Dosage and administration details
    Aflibercept ophthalmic solution, 2 mg/50 µL dose, administered as a single IVT injection at Day 0, Week 4, and Week 8, followed by q8w maintenance regimen until study exit.

    Number of subjects in period 1
    		Brolucizumab 6 mg Aflibercept 2 mg
    Started
    370
    369
    Completed
    342
    329
    Not completed
    28
    40
         Adverse event, serious fatal
    4
    7
         Consent withdrawn by subject
    12
    21
         Physician decision
    -
    1
         Adverse event, non-fatal
    8
    3
         Lost to follow-up
    1
    6
         Other - not specified
    3
    -
         Lack of efficacy
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brolucizumab 6 mg
    Reporting group description
    		 Single intravitreal (IVT) injection of brolucizumab ophthalmic solution at Day 0, Week 4, and Week 8, followed by q8w/q12w maintenance regimen until study exit

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 Single IVT injection of aflibercept ophthalmic solution at Day 0, Week 4, and Week 8, followed by q8w maintenance regimen until study exit

    Reporting group values
    		 Brolucizumab 6 mg Aflibercept 2 mg Total
    Number of subjects
    		 370 369 739
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.8 ± 8.58 75.5 ± 7.87 -
    Gender categorical
    Units: Subjects
        Female
    		 210 212 422
        Male
    		 160 157 317

    End points

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    End points reporting groups
    Reporting group title
    Brolucizumab 6 mg
    Reporting group description
    		 Single intravitreal (IVT) injection of brolucizumab ophthalmic solution at Day 0, Week 4, and Week 8, followed by q8w/q12w maintenance regimen until study exit

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 Single IVT injection of aflibercept ophthalmic solution at Day 0, Week 4, and Week 8, followed by q8w maintenance regimen until study exit

    Primary: Change From Baseline in Best Corrected Visual Acuity (BCVA) (Letters Read) at Week 48 - Study Eye

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    End point title
    		 Change From Baseline in Best Corrected Visual Acuity (BCVA) (Letters Read) at Week 48 - Study Eye
    End point description
    BCVA (with spectacles or other visual corrective devices) was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) testing at 4 meters and reported in letters read correctly. Baseline was defined as the last measurement prior to first treatment. An increase (gain) in letters read from the baseline assessment indicates improvement. One eye (study eye) contributed to the analysis. Full Analysis Set (FAS) - Last Observation Carried Forward (LOCF). Results reported up to Week 48 are based on the database locked for the primary analysis at Week 48.
    End point type
    Primary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    370 [1]
    369 [2]
    Units: letters
        arithmetic mean (standard deviation)
    6.9 ± 11.47
    7.6 ± 12.47
    Notes
    [1] - Full Analysis Set (FAS) - Last Observation Carried Forward (LOCF)
    [2] - Full Analysis Set (FAS) - Last Observation Carried Forward (LOCF)
    Statistical analysis title
    		 Change from BL in BCVA at Week 48 - Study Eye
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    739
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 ANOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.86
    Notes
    [3] - The noninferiority margin was 4 letters.
    [4] - 1-sided p-value reported. Hypothesis tested according to pre-specified hierarchical testing that ensures global type I error rate at 0.05. Analyzed using ANOVA model with baseline BCVA categories, age categories, and treatment as fixed effect factors

    Secondary: Average Change From Baseline in BCVA (Letters Read) Over the Period Week 36 Through Week 48 - Study Eye

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    End point title
    		 Average Change From Baseline in BCVA (Letters Read) Over the Period Week 36 Through Week 48 - Study Eye
    End point description
    BCVA (with spectacles or other visual corrective devices) was assessed using ETDRS testing at 4 meters and reported in letters read correctly. Baseline was defined as the last measurement prior to first treatment. An increase (gain) in letters read from the baseline assessment indicates improvement. One eye (study eye) contributed to the analysis. Results reported up to Week 48 are based on the database locked for the primary analysis at Week 48.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 36, 40, 44, 48
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    370 [5]
    369 [6]
    Units: letters
        arithmetic mean (standard deviation)
    6.6 ± 11.10
    7.7 ± 11.81
    Notes
    [5] - FAS - LOCF
    [6] - FAS - LOCF
    Statistical analysis title
    		 Average Change From BL in BCVA - Weeks 36-48
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    739
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 = 0.0003 [8]
    Method
    		 ANOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.82
    Notes
    [7] - The non-inferiority margin was 4 letters.
    [8] - 1-sided p-value reported. Hypothesis tested according to pre-specified hierarchical testing that ensures global type I error rate at 0.05. Analyzed using ANOVA model with baseline BCVA categories, age categories, and treatment as fixed effect factors

    Secondary: Proportion of Subjects With Positive q12 Treatment Status at Week 48

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    End point title
    		 Proportion of Subjects With Positive q12 Treatment Status at Week 48 [9]
    End point description
    Positive q12 treatment status was defined as IVT injections per planned dosing regimen (one injection every 12 weeks “q12w”, after the initial three loading injections every 4 weeks “q4w”). A disease activity assessment (DAA) was performed at pre-specified visits (Weeks 16, 20, 28, 32, 40, 44) to identify q8w need. The estimate for the proportion of subjects with a positive q12w status at Week 48 were derived from Kaplan-Meier time to event analyses for the event of first q8w need, applying event allocations (in case of lack of efficacy and/or lack of safety=efficacy/safety approach) and censoring as described in the SAP. Censored subjects were considered to be not anymore under risk for a q8 need identification at later visits. Corresponding 95% Confidence Intervals (CIs) were derived from the LOGLOG transformation. This outcome measure was pre-specified for brolucizumab 6 mg arm only.
    End point type
    Secondary
    End point timeframe
    Weeks 16, 20, 28, 32, 40, 44, 48
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No hypothesis testing was performed.
    End point values
    		 Brolucizumab 6 mg
    Number of subjects analysed
    370 [10]
    Units: proportion of subjects
        number (confidence interval 95%)
    0.5101 (0.4567 to 0.5610)
    Notes
    [10] - FAS - efficacy/safety approach
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With Positive q12 Treatment Status at Week 48 Within the Subjects With no q8w Treatment Need During the Initial q12w Cycle

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    End point title
    		 Proportion of Subjects With Positive q12 Treatment Status at Week 48 Within the Subjects With no q8w Treatment Need During the Initial q12w Cycle [11]
    End point description
    Positive q12 treatment status was defined as IVT injections per planned dosing regimen (one injection every 12 weeks “q12w”, after the initial three loading injections every 4 weeks “q4w”). A disease activity assessment (DAA) was performed at pre-specified visits (Weeks 16, 20, 28, 32, 40, 44) to identify q8w need. The estimate for the proportion of subjects with a positive q12w status at Week 48 were derived from Kaplan-Meier time to event analyses for the event of first q8w need, applying event allocations (in case of lack of efficacy and/or lack of safety=efficacy/safety approach) and censoring as described in the SAP. Censored subjects were considered to be not anymore under risk for a q8 need identification at later visits. Corresponding 95% Confidence Intervals (CIs) were derived from the LOGLOG transformation. This outcome measure was pre-specified for brolucizumab 6 mg arm only.
    End point type
    Secondary
    End point timeframe
    Weeks 16, 20, 28, 32, 40, 44, 48
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No hypothesis testing was performed.
    End point values
    		 Brolucizumab 6 mg
    Number of subjects analysed
    220 [12]
    Units: proportion of subjects
        number (confidence interval 95%)
    0.8170 (0.7582 to 0.8629)
    Notes
    [12] - FAS - efficacy/safety approach
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AE) were collected for the duration of enrollment in the study.
    Adverse event reporting additional description
    AEs were obtained through solicited and spontaneous comments from subjects and through observations by the Investigator as outlined in the study protocol. This analysis population includes all subjects who received at least 1 IVT injection (Safety Analysis Set).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    RTH258 6mg
    Reporting group description
    		 RTH258 6mg

    Reporting group title
    Aflibercept 2mg
    Reporting group description
    		 Aflibercept 2mg

    Serious adverse events
    		 RTH258 6mg Aflibercept 2mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    79 / 370 (21.35%)
    89 / 369 (24.12%)
         number of deaths (all causes)
    4
    7
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 370 (0.54%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip surgery
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implantable defibrillator replacement
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein operation
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cyst
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 370 (0.00%)
    3 / 369 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Pyrexia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 370 (0.54%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Charles Bonnet syndrome
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental fatigue
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood disorder due to a general medical condition
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paranoid personality disorder
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Investigation
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cataract traumatic - Study eye
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Facial bones fracture
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    3 / 370 (0.81%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 370 (0.54%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parasystole
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 370 (0.00%)
    4 / 369 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 370 (0.54%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 370 (0.81%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Anterior chamber inflammation - Study eye
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blindness - Study eye
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dry age-related macular degeneration - Study eye
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery embolism - Study eye
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion - Study eye
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery thrombosis - Study eye
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment - Study eye
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal pigment epithelial tear - Study eye
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear - Study eye
         subjects affected / exposed
    2 / 370 (0.54%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis - Study eye
         subjects affected / exposed
    3 / 370 (0.81%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual acuity reduced - Study eye
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis haemorrhagic
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal polyp
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar hernia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 370 (0.54%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Neuropathic ulcer
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary bladder polyp
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder rupture
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryocystitis - Study eye
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis - Study eye
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 370 (0.54%)
    8 / 369 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 369 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 RTH258 6mg Aflibercept 2mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    176 / 370 (47.57%)
    194 / 369 (52.57%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    28 / 370 (7.57%)
    25 / 369 (6.78%)
         occurrences all number
    34
    28
    Eye disorders
    Cataract - Fellow eye
         subjects affected / exposed
    7 / 370 (1.89%)
    22 / 369 (5.96%)
         occurrences all number
    7
    22
    Cataract - Study eye
         subjects affected / exposed
    11 / 370 (2.97%)
    43 / 369 (11.65%)
         occurrences all number
    11
    43
    Conjunctival haemorrhage - Study eye
         subjects affected / exposed
    17 / 370 (4.59%)
    19 / 369 (5.15%)
         occurrences all number
    19
    21
    Eye pain - Study eye
         subjects affected / exposed
    13 / 370 (3.51%)
    19 / 369 (5.15%)
         occurrences all number
    19
    26
    Neovascular age-related macular degeneration - Fellow eye
         subjects affected / exposed
    31 / 370 (8.38%)
    32 / 369 (8.67%)
         occurrences all number
    33
    32
    Visual acuity reduced - Study eye
         subjects affected / exposed
    31 / 370 (8.38%)
    25 / 369 (6.78%)
         occurrences all number
    38
    38
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    16 / 370 (4.32%)
    28 / 369 (7.59%)
         occurrences all number
    20
    33
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    22 / 370 (5.95%)
    20 / 369 (5.42%)
         occurrences all number
    31
    23
    Influenza
         subjects affected / exposed
    24 / 370 (6.49%)
    27 / 369 (7.32%)
         occurrences all number
    24
    29
    Nasopharyngitis
         subjects affected / exposed
    43 / 370 (11.62%)
    31 / 369 (8.40%)
         occurrences all number
    60
    42

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Aug 2015
    To clarify some inclusion/exclusion criteria and study procedures, and to allow unrestricted access to standard of care therapy for the fellow eye
    10 Feb 2017
    To allow ADA analysis of the samples collected from subjects treated with aflibercept 2 mg

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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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