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    Clinical Trial Results:
    Managing neovascular age-related macular degeneration (nAMD) over 2 years with a Treat and Extend (T&E) regimen of 2 mg intravitreal aflibercept - a randomized, open-label, active-controlled, parallel-group phase IV/IIIb study (ARIES)

    Summary
    EudraCT number
    		 2014-003132-39
    Trial protocol
    		 GB   ES   FR   IT  
    Global end of trial date
    26 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 May 2020
    First version publication date
    08 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY 86-5321/17508
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02581891
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    27 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether 2 mg Intravitreal (IVT) aflibercept administered in an early-start T&E regimen (initiated after the first 8-weekly treatment interval) is non-inferior to 2 mg IVT aflibercept administered in a late-start T&E regimen (initiated at the end of Year 1, per current label at that time) in subjects with nAMD.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 34
    Country: Number of subjects enrolled
    Canada: 30
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 48
    Country: Number of subjects enrolled
    Hungary: 80
    Country: Number of subjects enrolled
    Italy: 46
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    United Kingdom: 16
    Worldwide total number of subjects
    287
    EEA total number of subjects
    257
    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)
    26
    From 65 to 84 years
    212
    85 years and over
    49

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted from 19-Nov-2015 (First Patient First Visit) to 26-Apr-2019 (Last Patient Last Visit).

    Pre-assignment
    Screening details
    		 A total of 443 participants were enrolled in this study. Of these, 156 participants were screening failures and did not enter the treatment period. Of the 287 treated participants, 16 were treated during the initiation phase, but were not randomized to a treatment arm after the initiation phase.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Early-start T&E arm
    Arm description
    		 All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    Eylea
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    The volume of injection was 50 μL (0.05 mL) for the 2 mg aflibercept dose, and was administered via IVT injection to the study eye.

    Arm title
    		 Late-start T&E arm
    Arm description
    		 All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    Eylea
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    The volume of injection was 50 μL (0.05 mL) for the 2 mg aflibercept dose, and was administered via IVT injection to the study eye.

    Number of subjects in period 1 [1]
    		Early-start T&E arm Late-start T&E arm
    Started
    135
    136
    Completed treatment
    120
    117
    Completed
    119
    117
    Not completed
    16
    19
         Adverse event, serious fatal
    3
    4
         Discontinued during followup
    1
    -
         Consent withdrawn by subject
    4
    5
         Physician decision
    -
    1
         Adverse event, non-fatal
    4
    6
         Other Reasons
    3
    1
         Lost to follow-up
    1
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Sixteen participants who were treated in initiation phase were not randomized and allocated to a treatment arm.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Early-start T&E arm
    Reporting group description
    		 All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.

    Reporting group title
    Late-start T&E arm
    Reporting group description
    		 All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.

    Reporting group values
    		 Early-start T&E arm Late-start T&E arm Total
    Number of subjects
    		 135 136 271
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 16 9 25
        From 65-84 years
    		 95 106 201
        85 years and over
    		 24 21 45
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 76 ( 8.8 ) 76.9 ( 8.2 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 81 73 154
        Male
    		 54 63 117
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 2 1 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 0 1
        White
    		 131 127 258
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 8 9
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 7 10
        Not Hispanic or Latino
    		 126 122 248
        Unknown or Not Reported
    		 6 7 13
    Baseline BCVA letters scores (study eye)
    BCVA = best corrected visual acuity
    Units: letters
        arithmetic mean (standard deviation)
    		 60.2 ( 12.1 ) 61.3 ( 10.8 ) -
    Baseline CRT
    CRT = central retinal thickness
    Units: μm
        arithmetic mean (standard deviation)
    		 443.7 ( 120.0 ) 448.3 ( 133.1 ) -
    BCVA letters scores at Week 16 (study eye)
    BCVA = best corrected visual acuity
    Units: letters
        arithmetic mean (standard deviation)
    		 66.7 ( 13.0 ) 69.6 ( 11.6 ) -
    CRT at Week 16 (study eye)
    CRT = central retinal thickness
    Units: μm
        arithmetic mean (standard deviation)
    		 321.4 ( 93.4 ) 322.5 ( 104.0 ) -

    End points

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    End points reporting groups
    Reporting group title
    Early-start T&E arm
    Reporting group description
    		 All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.

    Reporting group title
    Late-start T&E arm
    Reporting group description
    		 All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all randomized subjects who received any study drug and have a BCVA assessment at Week 16 and at least 1 additional post-Week 16 BCVA assessment. The FAS were analyzed “as randomized”.

    Subject analysis set title
    Per-protocol Set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS includes all subjects in the FAS without any major protocol deviation. Additionally, injection-intensive subjects who needed injections at shorter intervals than 2Q8 between Week 16 and Week 52 were excluded from the PPS.

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAF includes all subjects who received any study drug under this protocol. In the safety analysis subjects who dropped out after start of treatment before randomization were described only in “total”, since no allocation of such subjects to a treatment arm is possible.

    Primary: Change in BCVA as measured by the ETDRS letter score

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    End point title
    		 Change in BCVA as measured by the ETDRS letter score
    End point description
    BCVA (best corrected visual acuity) was measured by the ETDRS (Early Treatment Diabetic Retinopathy Study) letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye at 4 meters; a higher score represents better functioning.
    End point type
    Primary
    End point timeframe
    From Week 16 to Week 104
    End point values
    		 Early-start T&E arm Late-start T&E arm
    Number of subjects analysed
    106 [1]
    104 [2]
    Units: Letters correctly read
        arithmetic mean (standard deviation)
    -2.1 ( 11.4 )
    -0.4 ( 8.4 )
    Notes
    [1] - PPS
    [2] - PPS
    Statistical analysis title
    		 Analysis of covariance for BCVA change
    Comparison groups
    Early-start T&E arm v Late-start T&E arm
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.0162
    Method
    		 ANCOVA
    Parameter type
    		 LS means difference
    Point estimate
    -2.0199
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.747
         upper limit
    		 0.7073
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.3833
    Notes
    [3] - The non-inferiority margin is set to 5 letters.

    Secondary: Percentage of participants maintaining vision (<3 lines loss) at Week 104 compared with baseline

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    End point title
    		 Percentage of participants maintaining vision (<3 lines loss) at Week 104 compared with baseline
    End point description
    Participants maintained 3 lines (15 letters) vision loss in BCVA (Best-corrected visual acuity) as measured by the ETDRS (Early Treatment Diabetic Retinopathy Study) letter.
    End point type
    Secondary
    End point timeframe
    at Week 104
    End point values
    		 Early-start T&E arm Late-start T&E arm
    Number of subjects analysed
    106 [4]
    104 [5]
    Units: Percentage
        number (not applicable)
    93.4
    96.2
    Notes
    [4] - PPS
    [5] - PPS
    No statistical analyses for this end point

    Secondary: Change in BCVA from baseline to Week 52, baseline to Week 104, and Week 16 to Week 52

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    End point title
    		 Change in BCVA from baseline to Week 52, baseline to Week 104, and Week 16 to Week 52
    End point description
    BCVA (best corrected visual acuity) was measured by the ETDRS (Early Treatment Diabetic Retinopathy Study) letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye at 4 meters; a higher score represents better functioning.
    End point type
    Secondary
    End point timeframe
    from baseline to Week 52, baseline to Week 104, and Week 16 to Week 52
    End point values
    		 Early-start T&E arm Late-start T&E arm
    Number of subjects analysed
    106 [6]
    104 [7]
    Units: Letters
    arithmetic mean (standard deviation)
        From baseline to Week 52
    7.8 ( 9.4 )
    10.2 ( 9.3 )
        From baseline to Week 104
    4.3 ( 13.4 )
    7.9 ( 11.9 )
        From Week 16 to Week 52
    1.3 ( 6.4 )
    2.0 ( 5.3 )
    Notes
    [6] - PPS
    [7] - PPS
    No statistical analyses for this end point

    Secondary: Percentage of participants maintaining vision (<3 lines loss) at Week 52 compared with baseline

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    End point title
    		 Percentage of participants maintaining vision (<3 lines loss) at Week 52 compared with baseline
    End point description
    Participants maintained 3 lines (15 letters) vision loss in BCVA (Best-corrected visual acuity) as measured by the ETDRS (Early Treatment Diabetic Retinopathy Study) letter.
    End point type
    Secondary
    End point timeframe
    At week 52
    End point values
    		 Early-start T&E arm Late-start T&E arm
    Number of subjects analysed
    106 [8]
    104 [9]
    Units: Percentage
        number (not applicable)
    100.0
    100.0
    Notes
    [8] - PPS
    [9] - PPS
    No statistical analyses for this end point

    Secondary: Percentage of participants gained 3-line at Week 52 and Week 104 compared with baseline

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    End point title
    		 Percentage of participants gained 3-line at Week 52 and Week 104 compared with baseline
    End point description
    Participants gained 3 lines (15 letters) in BCVA (Best-corrected visual acuity) as measured by the ETDRS (Early Treatment Diabetic Retinopathy Study) letter.
    End point type
    Secondary
    End point timeframe
    At Week 52 and Week 104
    End point values
    		 Early-start T&E arm Late-start T&E arm
    Number of subjects analysed
    106 [10]
    104 [11]
    Units: Percentage
    number (not applicable)
        Week 52
    19.8
    27.9
        Week 104
    18.9
    22.1
    Notes
    [10] - PPS
    [11] - PPS
    No statistical analyses for this end point

    Secondary: Change in Central Retinal Thickness (CRT)

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    End point title
    		 Change in Central Retinal Thickness (CRT)
    End point description
    CRT were evaluated using spectral domain Optical coherence tomograph (OCT).
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52, baseline to Week 104, Week 16 to Week 52, and Week 16 to Week 104
    End point values
    		 Early-start T&E arm Late-start T&E arm
    Number of subjects analysed
    106 [12]
    104 [13]
    Units: Letters
    arithmetic mean (standard deviation)
        From baseline to Week 52
    -164.9 ( 117.3 )
    -167.1 ( 117.1 )
        From baseline to Week 104
    -161.6 ( 135.6 )
    -158.6 ( 125.1 )
        From Week 16 to Week 52
    -28.5 ( 56.3 )
    -28.7 ( 54.0 )
        From Week 16 to Week 104
    -25.1 ( 68.9 )
    -20.2 ( 70.0 )
    Notes
    [12] - PPS
    [13] - PPS
    No statistical analyses for this end point

    Secondary: Number of study drug injections from baseline to Week 52 and baseline to Week 104

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    End point title
    		 Number of study drug injections from baseline to Week 52 and baseline to Week 104
    End point description
    End point type
    Secondary
    End point timeframe
    At Week 52 and Week 104
    End point values
    		 Early-start T&E arm Late-start T&E arm
    Number of subjects analysed
    106 [14]
    104 [15]
    Units: injections
    arithmetic mean (standard deviation)
        Week 52
    7.1 ( 0.8 )
    8.0 ( 0.2 )
        Week 104
    12.0 ( 2.3 )
    13.0 ( 1.8 )
    Notes
    [14] - PPS
    [15] - PPS
    No statistical analyses for this end point

    Secondary: Duration of last treatment interval

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    End point title
    		 Duration of last treatment interval
    End point description
    End point type
    Secondary
    End point timeframe
    Early-Start T&E: from week 16 up to Week 104 or early termination; Late-Start T&E: From end of Year 1 up to Week 104 or early termination
    End point values
    		 Early-start T&E arm Late-start T&E arm
    Number of subjects analysed
    106 [16]
    104 [17]
    Units: Weeks
        arithmetic mean (standard deviation)
    11.5445 ( 3.7336 )
    11.3819 ( 3.6845 )
    Notes
    [16] - PPS
    [17] - PPS
    No statistical analyses for this end point

    Secondary: Percentage of participants requiring retreatment at 8 weeks, 10 weeks, 12 weeks, 14 weeks, and 16 weeks as the last treatment interval

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    End point title
    		 Percentage of participants requiring retreatment at 8 weeks, 10 weeks, 12 weeks, 14 weeks, and 16 weeks as the last treatment interval
    End point description
    End point type
    Secondary
    End point timeframe
    at 8 weeks, 10 weeks, 12 weeks, 14 weeks, and 16 weeks
    End point values
    		 Early-start T&E arm Late-start T&E arm
    Number of subjects analysed
    106 [18]
    104 [19]
    Units: percentage
    number (not applicable)
        <8 weeks
    5.7
    7.7
        8 weeks
    27.4
    29.8
        10 weeks
    19.8
    10.6
        12 weeks
    8.5
    13.5
        14 weeks
    8.5
    11.5
        16 weeks
    25.5
    25.0
        >16 weeks
    4.7
    1.9
    Notes
    [18] - PPS
    [19] - PPS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) were AEs that started after the first application of aflibercept up to 30 days after last study drug Injection in the study. TEAEs were collected Week 0 till End of study/Week 104 or early termination.
    Adverse event reporting additional description
    Below adverse events were reported based on Safety Analysis Set (SAF), which included all participants who received any study drug in this study. The participants who dropped out after start of treatment before randomization were not allocated to a treatment arm, but were included in this SAF.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Early-start T&E arm
    Reporting group description
    		 All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.

    Reporting group title
    Late-start T&E arm
    Reporting group description
    		 All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.

    Reporting group title
    Treated, but not randomized
    Reporting group description
    		 Participants were treated during the initiation phase, received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4 and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks)at Week 16, but were not randomized to a treatment arm after the initiation phase.

    Serious adverse events
    		 Early-start T&E arm Late-start T&E arm Treated, but not randomized
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 135 (21.48%)
    35 / 136 (25.74%)
    3 / 16 (18.75%)
         number of deaths (all causes)
    3
    4
    0
         number of deaths resulting from adverse events
    1
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Basal cell carcinoma
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Bladder neoplasm
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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 neoplasm malignant
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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 neoplasm
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Epithelioid mesothelioma
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Papillary renal cell carcinoma
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Aortic dissection
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Haematoma
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Hypovolaemic shock
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Intermittent claudication
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Extremity necrosis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Surgical and medical procedures
    Implantable defibrillator replacement
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    General disorders and administration site conditions
    Hernia
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Pyrexia
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Cough
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Dyspnoea
         subjects affected / exposed
    0 / 135 (0.00%)
    2 / 136 (1.47%)
    0 / 16 (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
    Pleural effusion
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Facial bones fracture
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Hip fracture
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Rib fracture
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Splenic rupture
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Traumatic fracture
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Inflammation of wound
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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 / 135 (0.00%)
    1 / 136 (0.74%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Atrial flutter
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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 arrest
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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 failure congestive
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 136 (0.00%)
    0 / 16 (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
    Cor pulmonale acute
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Coronary artery stenosis
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Pericardial haemorrhage
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Ventricular tachycardia
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Cardiac valve disease
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Cerebral infarction
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    2 / 16 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Hemiplegia
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Eye disorders
    Eye inflammation
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Retinal artery embolism
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Visual acuity reduced
         subjects affected / exposed
    0 / 135 (0.00%)
    2 / 136 (1.47%)
    0 / 16 (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
    Visual impairment
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Eyelid cyst
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 136 (0.00%)
    0 / 16 (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
    Constipation
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Gastritis
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 136 (0.74%)
    0 / 16 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Ileus
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Inguinal hernia
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 136 (0.74%)
    0 / 16 (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
    Intestinal perforation
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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 acute
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Small intestinal obstruction
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Large intestine polyp
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Noninfective sialoadenitis
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Acute hepatic failure
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Biliary colic
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Cholangitis
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Cholecystitis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Cholecystitis acute
         subjects affected / exposed
    2 / 135 (1.48%)
    2 / 136 (1.47%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 136 (0.74%)
    0 / 16 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    End stage renal disease
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Fracture pain
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Bronchitis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Cystitis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Influenza
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 136 (0.00%)
    0 / 16 (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
    Pneumonia
         subjects affected / exposed
    3 / 135 (2.22%)
    5 / 136 (3.68%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Sepsis
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 136 (0.74%)
    0 / 16 (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
    Enterococcal sepsis
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 136 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 136 (0.00%)
    0 / 16 (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
    Fluid overload
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 136 (0.74%)
    0 / 16 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Early-start T&E arm Late-start T&E arm Treated, but not randomized
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 135 (68.89%)
    80 / 136 (58.82%)
    10 / 16 (62.50%)
    Injury, poisoning and procedural complications
    Foreign body in eye
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 136 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Post procedural swelling
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 136 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 135 (9.63%)
    11 / 136 (8.09%)
    0 / 16 (0.00%)
         occurrences all number
    15
    11
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    2 / 135 (1.48%)
    11 / 136 (8.09%)
    0 / 16 (0.00%)
         occurrences all number
    6
    25
    0
    Cataract
         subjects affected / exposed
    9 / 135 (6.67%)
    8 / 136 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    14
    13
    0
    Cataract nuclear
         subjects affected / exposed
    2 / 135 (1.48%)
    7 / 136 (5.15%)
    0 / 16 (0.00%)
         occurrences all number
    4
    16
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    20 / 135 (14.81%)
    18 / 136 (13.24%)
    0 / 16 (0.00%)
         occurrences all number
    26
    20
    0
    Corneal erosion
         subjects affected / exposed
    5 / 135 (3.70%)
    2 / 136 (1.47%)
    1 / 16 (6.25%)
         occurrences all number
    6
    3
    1
    Dry eye
         subjects affected / exposed
    6 / 135 (4.44%)
    11 / 136 (8.09%)
    0 / 16 (0.00%)
         occurrences all number
    11
    18
    0
    Erythema of eyelid
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 136 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Macular degeneration
         subjects affected / exposed
    6 / 135 (4.44%)
    5 / 136 (3.68%)
    1 / 16 (6.25%)
         occurrences all number
    6
    5
    1
    Punctate keratitis
         subjects affected / exposed
    10 / 135 (7.41%)
    5 / 136 (3.68%)
    1 / 16 (6.25%)
         occurrences all number
    23
    9
    1
    Retinal haemorrhage
         subjects affected / exposed
    4 / 135 (2.96%)
    6 / 136 (4.41%)
    2 / 16 (12.50%)
         occurrences all number
    4
    7
    2
    Swelling of eyelid
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 136 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Visual acuity reduced
         subjects affected / exposed
    21 / 135 (15.56%)
    17 / 136 (12.50%)
    1 / 16 (6.25%)
         occurrences all number
    24
    19
    1
    Visual impairment
         subjects affected / exposed
    8 / 135 (5.93%)
    4 / 136 (2.94%)
    0 / 16 (0.00%)
         occurrences all number
    11
    4
    0
    Vitreous floaters
         subjects affected / exposed
    8 / 135 (5.93%)
    4 / 136 (2.94%)
    0 / 16 (0.00%)
         occurrences all number
    8
    5
    0
    Vitreous adhesions
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 136 (1.47%)
    1 / 16 (6.25%)
         occurrences all number
    1
    2
    1
    Choroidal neovascularisation
         subjects affected / exposed
    7 / 135 (5.19%)
    5 / 136 (3.68%)
    0 / 16 (0.00%)
         occurrences all number
    7
    5
    0
    Retinal pigment epithelial tear
         subjects affected / exposed
    3 / 135 (2.22%)
    2 / 136 (1.47%)
    1 / 16 (6.25%)
         occurrences all number
    3
    2
    1
    Neovascular age-related macular degeneration
         subjects affected / exposed
    15 / 135 (11.11%)
    14 / 136 (10.29%)
    1 / 16 (6.25%)
         occurrences all number
    15
    14
    1
    Macular fibrosis
         subjects affected / exposed
    2 / 135 (1.48%)
    6 / 136 (4.41%)
    1 / 16 (6.25%)
         occurrences all number
    2
    6
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 135 (5.93%)
    1 / 136 (0.74%)
    0 / 16 (0.00%)
         occurrences all number
    9
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 136 (1.47%)
    1 / 16 (6.25%)
         occurrences all number
    1
    2
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 135 (0.00%)
    3 / 136 (2.21%)
    1 / 16 (6.25%)
         occurrences all number
    0
    3
    1
    Influenza
         subjects affected / exposed
    11 / 135 (8.15%)
    12 / 136 (8.82%)
    0 / 16 (0.00%)
         occurrences all number
    12
    13
    0
    Nasopharyngitis
         subjects affected / exposed
    18 / 135 (13.33%)
    17 / 136 (12.50%)
    0 / 16 (0.00%)
         occurrences all number
    21
    22
    0
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 136 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2016
    Major modifications included the following: • The special case of a diagnosis of “completely dry” was added to the early start T&E arm, • anatomical criteria for extending the treatment intervals were clarified, • the option of not extending the treatment interval, even if all anatomical criteria are met, was removed, • the specification of Choroidal neovascularization (CNV) lesions were simplified (Inclusion criterion 3), and the percentage of total lesions for scar or fibrosis was reduced (Exclusion criterion 6).

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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