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    Clinical Trial Results:
    A Multicenter, Open-Label Extension Study to Evaluate the Long-Term Safety and Tolerability of Lampalizumab in Patients with Geographic Atrophy Secondary to Age-Related Macular Degeneration who have Completed a Roche-Sponsored Study

    Summary
    EudraCT number
    		 2016-000423-13
    Trial protocol
    		 GB   PT   HU   DK   AT   SE   DE   PL   ES   SK   BE   FR   NL   IT  
    Global end of trial date
    31 Jan 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    GX30191
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02745119
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the long-term safety and tolerability of intravitreal (ITV) injections of lampalizumab, 10 milligrams (mg) administered to subjects with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jul 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 576
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Switzerland: 13
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Slovakia: 8
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Austria: 26
    Worldwide total number of subjects
    842
    EEA total number of subjects
    230
    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)
    36
    From 65 to 84 years
    569
    85 years and over
    237

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 994 subjects were enrolled in the study at 202 investigational sites across 19 countries. The study was terminated early by the Sponsor due to lack of efficacy.

    Pre-assignment
    Screening details
    		 Eligible subjects were those who enrolled in Studies GX29176 (NCT02247479) and GX29185 (NCT02247531) and had completed the 96-week treatment period without early treatment discontinuation or study discontinuation.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lampalizumab Q4W - Treatment-Naive
    Arm description
    		 Subjects who received sham comparator every 4 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 milligrams (mg), by intravitreal (ITV) injection, administered every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lampalizumab
    Investigational medicinal product code
    RO5490249
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Subjects who received sham comparator every 4 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by intravitreal (ITV) injection, administered every 4 weeks.

    Arm title
    		 Lampalizumab Q4W – Previously Treated
    Arm description
    		 Subjects who received lampalizumab every 4 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lampalizumab
    Investigational medicinal product code
    RO5490249
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Subjects who received lampalizumab every 4 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 4 weeks.

    Arm title
    		 Lampalizumab Q6W - Treatment-Naive
    Arm description
    		 Subjects who received sham comparator every 6 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lampalizumab
    Investigational medicinal product code
    RO5490249
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Subjects who received sham comparator every 6 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 6 weeks.

    Arm title
    		 Lampalizumab Q6W – Previously Treated
    Arm description
    		 Subjects who received lampalizumab every 6 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lampalizumab
    Investigational medicinal product code
    RO5490249
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Subjects who received lampalizumab every 6 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 6 weeks.

    Number of subjects in period 1
    		Lampalizumab Q4W - Treatment-Naive Lampalizumab Q4W – Previously Treated Lampalizumab Q6W - Treatment-Naive Lampalizumab Q6W – Previously Treated
    Started
    145
    274
    146
    277
    Completed
    0
    0
    0
    0
    Not completed
    145
    274
    146
    277
         Consent withdrawn by subject
    7
    15
    8
    14
         Physician decision
    -
    2
    2
    2
         Protocol Deviation
    -
    -
    -
    1
         Death
    3
    3
    -
    4
         Reason Not Specified
    -
    2
    -
    1
         Adverse event
    1
    -
    1
    3
         Study Terminated by Sponsor
    134
    252
    135
    251
         Lost to follow-up
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lampalizumab Q4W - Treatment-Naive
    Reporting group description
    		 Subjects who received sham comparator every 4 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 milligrams (mg), by intravitreal (ITV) injection, administered every 4 weeks.

    Reporting group title
    Lampalizumab Q4W – Previously Treated
    Reporting group description
    		 Subjects who received lampalizumab every 4 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 4 weeks.

    Reporting group title
    Lampalizumab Q6W - Treatment-Naive
    Reporting group description
    		 Subjects who received sham comparator every 6 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 6 weeks.

    Reporting group title
    Lampalizumab Q6W – Previously Treated
    Reporting group description
    		 Subjects who received lampalizumab every 6 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 6 weeks.

    Reporting group values
    		 Lampalizumab Q4W - Treatment-Naive Lampalizumab Q4W – Previously Treated Lampalizumab Q6W - Treatment-Naive Lampalizumab Q6W – Previously Treated Total
    Number of subjects
    		 145 274 146 277 842
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 79.0 ± 8.2 78.7 ± 7.8 79.2 ± 8.6 80.2 ± 7.9 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 82 167 79 164 492
        Male
    		 63 107 67 113 350

    End points

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    End points reporting groups
    Reporting group title
    Lampalizumab Q4W - Treatment-Naive
    Reporting group description
    		 Subjects who received sham comparator every 4 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 milligrams (mg), by intravitreal (ITV) injection, administered every 4 weeks.

    Reporting group title
    Lampalizumab Q4W – Previously Treated
    Reporting group description
    		 Subjects who received lampalizumab every 4 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 4 weeks.

    Reporting group title
    Lampalizumab Q6W - Treatment-Naive
    Reporting group description
    		 Subjects who received sham comparator every 6 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 6 weeks.

    Reporting group title
    Lampalizumab Q6W – Previously Treated
    Reporting group description
    		 Subjects who received lampalizumab every 6 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 6 weeks.

    Subject analysis set title
    All Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects in the study received lampalizumab 10 mg, ITV, Q4W or Q6W.

    Primary: Percentage of Subjects with Ocular Adverse Events (AEs) by Severity

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    End point title
    		 Percentage of Subjects with Ocular Adverse Events (AEs) by Severity [1]
    End point description
    An AE was defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether considered related to the medicinal product, any new disease or exacerbation of an existing disease, recurrence of an intermittent medical condition, or any deterioration in a laboratory value or other clinical test. Ocular AEs are the events which are localized in the ocular region. The safety-evaluable population included all subjects who enrolled in the extension study and received at least one lampalizumab injection in the extension study.
    End point type
    Primary
    End point timeframe
    Up to approximately one year
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only
    End point values
    		 Lampalizumab Q4W - Treatment-Naive Lampalizumab Q4W – Previously Treated Lampalizumab Q6W - Treatment-Naive Lampalizumab Q6W – Previously Treated All Subjects
    Number of subjects analysed
    145
    274
    146
    277
    842
    Units: percentage of subjects
    number (not applicable)
        Any severity
    37.2
    40.1
    24.7
    33.2
    34.7
        Mild
    25.5
    26.6
    16.4
    21.7
    23.0
        Moderate
    9.7
    11.3
    8.2
    10.1
    10.1
        Severe
    2.1
    2.2
    0
    1.4
    1.5
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Systemic (Non-Ocular) AEs by Severity

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    End point title
    		 Percentage of Subjects with Systemic (Non-Ocular) AEs by Severity [2]
    End point description
    An AE was defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether considered related to the medicinal product, any new disease or exacerbation of an existing disease, recurrence of an intermittent medical condition, or any deterioration in a laboratory value or other clinical test. The safety-evaluable population included all subjects who enrolled in the extension study and received at least one lampalizumab injection in the extension study.
    End point type
    Primary
    End point timeframe
    Up to approximately one year
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only
    End point values
    		 Lampalizumab Q4W - Treatment-Naive Lampalizumab Q4W – Previously Treated Lampalizumab Q6W - Treatment-Naive Lampalizumab Q6W – Previously Treated All Subjects
    Number of subjects analysed
    145
    274
    146
    277
    842
    Units: percentage of subjects
    number (not applicable)
        Any severity
    55.2
    54.0
    41.8
    51.3
    51.2
        Mild
    18.6
    20.1
    17.8
    20.9
    19.7
        Moderate
    28.3
    20.4
    18.5
    20.2
    21.4
        Severe
    8.3
    13.5
    5.5
    10.1
    10.1
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Anti-Lampalizumab Antibodies

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    End point title
    		 Percentage of Subjects with Anti-Lampalizumab Antibodies [3]
    End point description
    The immunogenicity analysis included subjects with at least one predose and one postdose anti-lampalizumab antibodies assessment. Predose was defined as prior to the first dose in the extension study for the prior sham subjects, and prior to the first dose in the parent study for the prior lampalizumab subjects. The safety-evaluable population included all subjects who enrolled in the extension study and received at least one lampalizumab injection in the extension study. Data is reported for evaluable subjects.
    End point type
    Primary
    End point timeframe
    Week 48
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only
    End point values
    		 Lampalizumab Q4W - Treatment-Naive Lampalizumab Q4W – Previously Treated Lampalizumab Q6W - Treatment-Naive Lampalizumab Q6W – Previously Treated All Subjects
    Number of subjects analysed
    1
    6
    2
    6
    15
    Units: percentage of subjects
        number (not applicable)
    0.0
    0.0
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately one year
    Adverse event reporting additional description
    The safety-evaluable population included all subjects who enrolled in the extension study and received at least one lampalizumab injection in the extension study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Lampalizumab Q4W - Treatment-Naive
    Reporting group description
    		 Subjects who received sham comparator every 4 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 milligrams (mg), by intravitreal (ITV) injection, administered every 4 weeks.

    Reporting group title
    Lampalizumab Q4W – Previously Treated
    Reporting group description
    		 Subjects who received lampalizumab every 4 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 4 weeks.

    Reporting group title
    Lampalizumab Q6W - Treatment-Naive
    Reporting group description
    		 Subjects who received sham comparator every 6 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 6 weeks.

    Reporting group title
    Lampalizumab Q6W – Previously Treated
    Reporting group description
    		 Subjects who received lampalizumab every 6 weeks in one of the parent studies and completed the Week 96 visit received lampalizumab, 10 mg, by ITV injection, administered every 6 weeks.

    Reporting group title
    All Subjects
    Reporting group description
    		 All subjects in the study received lampalizumab 10 mg, ITV, Q4W or Q6W.

    Serious adverse events
    		 Lampalizumab Q4W - Treatment-Naive Lampalizumab Q4W – Previously Treated Lampalizumab Q6W - Treatment-Naive Lampalizumab Q6W – Previously Treated All Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 145 (21.38%)
    58 / 274 (21.17%)
    14 / 146 (9.59%)
    50 / 277 (18.05%)
    153 / 842 (18.17%)
         number of deaths (all causes)
    3
    3
    0
    9
    15
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    1 / 146 (0.68%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    1 / 146 (0.68%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Basal cell carcinoma
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    1 / 146 (0.68%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Skin cancer
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the vulva
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Aortic calcification
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    1 / 146 (0.68%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    1 / 146 (0.68%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 145 (0.69%)
    2 / 274 (0.73%)
    1 / 146 (0.68%)
    1 / 277 (0.36%)
    5 / 842 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    3 / 277 (1.08%)
    4 / 842 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 4
    Oedema peripheral
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    2 / 277 (0.72%)
    3 / 842 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    1 / 146 (0.68%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    1 / 146 (0.68%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    1 / 146 (0.68%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    3 / 145 (2.07%)
    4 / 274 (1.46%)
    1 / 146 (0.68%)
    5 / 277 (1.81%)
    13 / 842 (1.54%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 5
    0 / 1
    2 / 10
    4 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood lactic acid increased
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Corneal abrasion
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    1 / 146 (0.68%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 145 (0.00%)
    4 / 274 (1.46%)
    1 / 146 (0.68%)
    5 / 277 (1.81%)
    10 / 842 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 2
    0 / 5
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Hip fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    1 / 146 (0.68%)
    2 / 277 (0.72%)
    3 / 842 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    3 / 274 (1.09%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    3 / 842 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    2 / 277 (0.72%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 145 (1.38%)
    3 / 274 (1.09%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    6 / 842 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    4 / 277 (1.44%)
    4 / 842 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Diastolic dysfunction
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 274 (0.73%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 274 (0.73%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral small vessel ischaemic disease
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia with lewy bodies
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wernicke's encephalopathy
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    1 / 145 (0.69%)
    4 / 274 (1.46%)
    1 / 146 (0.68%)
    2 / 277 (0.72%)
    8 / 842 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    1 / 1
    0 / 2
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neovascular age-related macular degeneration
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 274 (0.36%)
    1 / 146 (0.68%)
    2 / 277 (0.72%)
    5 / 842 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ocular hypertension
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 274 (0.73%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dellen
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dry age-related macular degeneration
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iritis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    2 / 277 (0.72%)
    3 / 842 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    2 / 277 (0.72%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal incarcerated hernia
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malabsorption
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    1 / 146 (0.68%)
    1 / 277 (0.36%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal artery stenosis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    1 / 146 (0.68%)
    1 / 277 (0.36%)
    3 / 842 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 274 (0.73%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    1 / 146 (0.68%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coccydynia
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint instability
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Endophthalmitis
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    1 / 146 (0.68%)
    1 / 277 (0.36%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 145 (2.07%)
    2 / 274 (0.73%)
    2 / 146 (1.37%)
    5 / 277 (1.81%)
    12 / 842 (1.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
    0 / 5
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 145 (1.38%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    2 / 277 (0.72%)
    5 / 842 (0.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 274 (0.73%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    3 / 842 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Bacteraemia
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system infection
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    1 / 146 (0.68%)
    1 / 277 (0.36%)
    3 / 842 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    2 / 842 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 274 (0.36%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    1 / 277 (0.36%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 274 (0.00%)
    0 / 146 (0.00%)
    0 / 277 (0.00%)
    1 / 842 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lampalizumab Q4W - Treatment-Naive Lampalizumab Q4W – Previously Treated Lampalizumab Q6W - Treatment-Naive Lampalizumab Q6W – Previously Treated All Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 145 (28.28%)
    63 / 274 (22.99%)
    26 / 146 (17.81%)
    56 / 277 (20.22%)
    186 / 842 (22.09%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    2 / 145 (1.38%)
    23 / 274 (8.39%)
    5 / 146 (3.42%)
    17 / 277 (6.14%)
    47 / 842 (5.58%)
         occurrences all number
    2
    34
    7
    22
    65
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    11 / 145 (7.59%)
    12 / 274 (4.38%)
    5 / 146 (3.42%)
    14 / 277 (5.05%)
    42 / 842 (4.99%)
         occurrences all number
    12
    16
    6
    14
    48
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    17 / 145 (11.72%)
    17 / 274 (6.20%)
    12 / 146 (8.22%)
    20 / 277 (7.22%)
    66 / 842 (7.84%)
         occurrences all number
    22
    20
    16
    25
    83
    Eye pain
         subjects affected / exposed
    8 / 145 (5.52%)
    8 / 274 (2.92%)
    5 / 146 (3.42%)
    11 / 277 (3.97%)
    32 / 842 (3.80%)
         occurrences all number
    8
    14
    6
    14
    42
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 145 (7.59%)
    12 / 274 (4.38%)
    3 / 146 (2.05%)
    6 / 277 (2.17%)
    32 / 842 (3.80%)
         occurrences all number
    12
    13
    3
    7
    35

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2017
    Added an independent Data Monitoring Committee to monitor subjects long-term safety following a recommendation from Ethics Committee; information regarding lampalizumab formulation, packaging, storage, and handling as well as reconstitution and study administration instructions were moved from Section 4.3.1 of the protocol to Appendices 4 to 6 to the Pharmacy Manual to assist sites in locating necessary information promptly; clarified the procedures across various protocol sections to aid the transition of subjects from the parent studies to this extension study (e.g., clarified the dose-interruption, treatment-discontinuation, and study-withdrawal criteria language; reorganized the study treatment discontinuation criteria; clarified the reporting requirements for serious adverse events (SAEs) and adverse events of special interest (AESIs) during the transition period between the parent study and this extension study.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated early by the Sponsor because the compound had demonstrated lack of efficacy. Thus, no participant in this study completed the full duration of treatment.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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