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    Clinical Trial Results:
    A Phase 3, Double-Blind, Randomized, Long-Term, Placebo-Controlled, Multicenter Study Evaluating the Safety and Efficacy of Obeticholic Acid in Subjects with Nonalcoholic Steatohepatitis

    Summary
    EudraCT number
    		 2015-002560-16
    Trial protocol
    		 GB   DE   AT   SE   BE   DK   ES   FI   PT   HU   PL  
    Global end of trial date
    15 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Sep 2024
    First version publication date
    14 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    747-303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02548351
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Intercept Pharmaceuticals, Inc.
    Sponsor organisation address
    305 Madison Avenue, Morristown, New Jersey, United States, 07960
    Public contact
    Medical Information, Intercept Pharmaceuticals, Inc., +1 8447824278, medinfo@interceptpharma.com
    Scientific contact
    Medical Information, Intercept Pharmaceuticals, Inc., +1 8447824278, medinfo@interceptpharma.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
    15 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary objective assessed of the trial were: ⦁ To evaluate the effect of OCA compared to placebo on all-cause mortality and liver‑related clinical outcomes as measured by the time to first occurrence of any of the following adjudicated events (clinical outcomes composite endpoint): ⦁ Death (all cause) ⦁ Model of end stage liver disease (MELD) score ≥15 ⦁ Liver transplant ⦁ Hospitalization (as defined by a stay of ≥24 hours) for onset of: ⦁ Variceal bleed ⦁ Hepatic encephalopathy (as defined by a West Haven score of ≥2) ⦁ Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) ⦁ Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or paracentesis) ⦁ Progression to cirrhosis
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Spain: 81
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    United Kingdom: 112
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Denmark: 24
    Country: Number of subjects enrolled
    Finland: 16
    Country: Number of subjects enrolled
    France: 126
    Country: Number of subjects enrolled
    Germany: 75
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 71
    Country: Number of subjects enrolled
    Australia: 69
    Country: Number of subjects enrolled
    Canada: 92
    Country: Number of subjects enrolled
    Switzerland: 21
    Country: Number of subjects enrolled
    Israel: 31
    Country: Number of subjects enrolled
    New Zealand: 20
    Country: Number of subjects enrolled
    Serbia: 6
    Country: Number of subjects enrolled
    United States: 1643
    Worldwide total number of subjects
    2477
    EEA total number of subjects
    483
    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)
    1961
    From 65 to 84 years
    516
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a phase 3, double-blind, randomized, long-term, placebo-controlled, multicenter study evaluating the safety and efficacy of Obeticholic Acid (OCA) in Participants with Nonalcoholic Steatohepatitis (NASH).

    Pre-assignment
    Screening details
    		 The study was conducted at approximately 350 investigational sites globally.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OCA 10 Milligrams (mg)
    Arm description
    		 Participants were randomized to receive OCA 10 mg once daily orally with water.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OCA 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered with OCA 10 mg tablets with water.

    Arm title
    		 OCA 25 mg
    Arm description
    		 Participants were randomized to receive OCA 25 mg once daily orally with water.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OCA 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered with OCA 25 mg tablets with water.

    Arm title
    		 Placebo
    Arm description
    		 Participants were randomized to receive matching placebo once daily orally with water.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered with matching placebo orally with water.

    Number of subjects in period 1
    		OCA 10 Milligrams (mg) OCA 25 mg Placebo
    Started
    825
    827
    825
    Completed
    0
    0
    0
    Not completed
    825
    827
    825
         Site Closure
    14
    5
    7
         Adverse event, serious fatal
    11
    15
    12
         Consent withdrawn by subject
    149
    154
    152
         Non-compliance with Study Drug
    4
    2
    -
         Physician decision
    11
    18
    11
         Study terminated by Sponsor
    549
    509
    528
         Adverse event, non-fatal
    22
    56
    36
         Unspecified
    19
    16
    20
         Lost to follow-up
    43
    50
    57
         Missing
    1
    1
    -
         Protocol deviation
    2
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OCA 10 Milligrams (mg)
    Reporting group description
    		 Participants were randomized to receive OCA 10 mg once daily orally with water.

    Reporting group title
    OCA 25 mg
    Reporting group description
    		 Participants were randomized to receive OCA 25 mg once daily orally with water.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomized to receive matching placebo once daily orally with water.

    Reporting group values
    		 OCA 10 Milligrams (mg) OCA 25 mg Placebo Total
    Number of subjects
    		 825 827 825 2477
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 655 643 663 1961
        From 65-84 years
    		 170 184 162 516
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.3 ( 10.76 ) 55.3 ( 11.71 ) 54.4 ( 11.21 ) -
    Gender categorical
    Units: Subjects
        Female
    		 475 494 347 1316
        Male
    		 350 333 478 1161

    End points

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    End points reporting groups
    Reporting group title
    OCA 10 Milligrams (mg)
    Reporting group description
    		 Participants were randomized to receive OCA 10 mg once daily orally with water.

    Reporting group title
    OCA 25 mg
    Reporting group description
    		 Participants were randomized to receive OCA 25 mg once daily orally with water.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomized to receive matching placebo once daily orally with water.

    Primary: Time to the First Adjudicated Event for Clinical Outcome Composite Endpoint: Percentage of Participants With an Event

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    End point title
    		 Time to the First Adjudicated Event for Clinical Outcome Composite Endpoint: Percentage of Participants With an Event
    End point description
    All potential liver-related clinical outcomes that occurred after administration of first dose of investigational product were reviewed and adjudicated by blinded, independent Hepatic Outcomes Committee (HOC). Adjudicated results were used to assess effect of OCA, compared to placebo in conjunction with established local standard of care, on clinical outcomes in participants with NASH as measured by time to first occurrence of any of following adjudicated events, derived as a composite event endpoint of death (all-cause), liver transplant, MELD ≥15 Score, hospitalization (defined by a stay of 24 hours or greater) for onset of: variceal bleed, hepatic encephalopathy (defined by a West Haven score of ≥2), and spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis), ascites secondary to cirrhosis requiring medical intervention, and histological progression to Cirrhosis. Clinical events distribution was estimated using Kaplan-Meier methodology.
    End point type
    Primary
    End point timeframe
    Up to 7 years
    End point values
    		 OCA 10 Milligrams (mg) OCA 25 mg Placebo
    Number of subjects analysed
    729
    730
    728
    Units: Percentage of participants with event
        number (confidence interval 95%)
    15.8 (13.2 to 18.6)
    14.7 (12.2 to 17.4)
    18.8 (16.0 to 21.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    OCA 10 Milligrams (mg) v Placebo
    Number of subjects included in analysis
    1457
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1028
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.814
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.635
         upper limit
    		 1.043
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    OCA 25 mg v Placebo
    Number of subjects included in analysis
    1458
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0444
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.772
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.994

    Secondary: Percentage of Responders With Improvement of Fibrosis by at Least One Stage With no Worsening of NASH Using Consensus Read Method of Scheduled Liver Biopsies

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    End point title
    		 Percentage of Responders With Improvement of Fibrosis by at Least One Stage With no Worsening of NASH Using Consensus Read Method of Scheduled Liver Biopsies
    End point description
    Fibrosis stage was evaluated by NASH Clinical Research Network (CRN) Fibrosis Staging System as follows: Stage 0: No fibrosis, Stage 1: Perisinusoidal/periportal fibrosis, Stage 1A: Mild, zone 3, perisinusoidal fibrosis, Stage 1B: Moderate, zone 3, perisinusoidal fibrosis, Stage 1C: Portal/periportal fibrosis, Stage 2: Perisinusoidal and portal/periportal fibrosis, Stage 3: Bridging fibrosis and Stage 4: Cirrhosis. No worsening of NASH was defined as no worsening of hepatocellular ballooning, no worsening of lobular inflammation, and no worsening of steatosis. Responders are defined as participants who did not discontinue treatment due to Adverse event (AE) or did not die and had evaluable post-Baseline biopsy assessment. Mantel-Haenszel method is used to construct the confidence intervals. Intent-to-Treat (ITT) Population comprised of all randomized participants with fibrosis stage 2 or stage 3 who receive at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 OCA 10 Milligrams (mg) OCA 25 mg Placebo
    Number of subjects analysed
    729
    730
    728
    Units: Percentage of participants
        number (not applicable)
    17.1
    19.5
    10.0
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    OCA 10 Milligrams (mg) v Placebo
    Number of subjects included in analysis
    1457
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    7.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.6
         upper limit
    		 10.6
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    OCA 25 mg v Placebo
    Number of subjects included in analysis
    1458
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    9.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.8
         upper limit
    		 13

    Secondary: Percentage of Participants Who Showed Improvement in Fibrosis by at Least 1 Stage and/or Resolution of NASH Without Worsening of Either Using Consensus Read Method

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    End point title
    		 Percentage of Participants Who Showed Improvement in Fibrosis by at Least 1 Stage and/or Resolution of NASH Without Worsening of Either Using Consensus Read Method
    End point description
    Fibrosis stage was evaluated by NASH Clinical Research Network (CRN) Fibrosis Staging System as follows: Stage 0: No fibrosis, Stage 1: Perisinusoidal/periportal fibrosis, Stage 1A: Mild, zone 3, perisinusoidal fibrosis, Stage 1B: Moderate, zone3, perisinusoidal fibrosis, Stage 1C: Portal/periportal fibrosis, Stage 2: Perisinusoidal and portal/periportal fibrosis, Stage 3: Bridging fibrosis and Stage 4: Cirrhosis. Resolution of NASH is defined as absence of fatty liver disease, or presence of simple or isolated steatosis without steatohepatitis, with a NAS (NAFLD Activity Score) of 0 for ballooning and 0-1 for inflammation. NAS ranges from 0-12; 0: no features of fatty liver disease and 12: highest degree of fatty liver disease. Higher scores signify worse symptoms. Responders are who did not discontinue treatment due to Adverse event (AE) or did not die and had evaluable post-Baseline biopsy assessment. Mantel-Haenszel method is used to construct confidence intervals
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 OCA 10 Milligrams (mg) OCA 25 mg Placebo
    Number of subjects analysed
    729
    730
    728
    Units: Percentage of participants
        number (not applicable)
    18.5
    20.8
    11.8
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    OCA 10 Milligrams (mg) v Placebo
    Number of subjects included in analysis
    1457
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0004
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    6.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3
         upper limit
    		 10.4
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    OCA 25 mg v Placebo
    Number of subjects included in analysis
    1458
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.2
         upper limit
    		 12.8

    Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A TEAE was defined as any AE that either newly appeared, increased in frequency, or worsened in severity following treatment up to 30 days from last dose of permanent investigational product discontinuation. Serious AE (SAE) was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event. Safety Population comprised all randomized participants, all fibrosis stages, who receive at least 1 dose of investigational product (OCA or placebo).
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 OCA 10 Milligrams (mg) OCA 25 mg Placebo
    Number of subjects analysed
    825
    827
    825
    Units: Participants
    number (not applicable)
        TEAEs
    798
    813
    781
        SAEs
    273
    276
    248
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 7 years
    Adverse event reporting additional description
    Treatment emergent adverse events and serious adverse events were collected in the Safety Population. Safety Population comprises of participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    OCA 10 Milligrams (mg)
    Reporting group description
    		 Participants were randomized to receive OCA 10 mg once daily orally with water.

    Reporting group title
    OCA 25 mg
    Reporting group description
    		 Participants were randomized to receive OCA 25 mg once daily orally with water.

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 OCA 10 Milligrams (mg) OCA 25 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    273 / 825 (33.09%)
    276 / 827 (33.37%)
    248 / 825 (30.06%)
         number of deaths (all causes)
    14
    19
    14
         number of deaths resulting from adverse events
    14
    19
    14
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of salivary gland
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal squamous cell carcinoma
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    0 / 825 (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
    Benign hepatic neoplasm
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm of spinal cord
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Benign salivary gland neoplasm
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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 transitional cell carcinoma
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma recurrent
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone cancer
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Breast cancer
         subjects affected / exposed
    4 / 825 (0.48%)
    2 / 827 (0.24%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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 recurrent
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Colon adenoma
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    0 / 825 (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
    Endometrial cancer
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer metastatic
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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 stromal tumour
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemangiopericytoma
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic neoplasm
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    8 / 825 (0.97%)
    6 / 827 (0.73%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 9
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal papillary mucinous neoplasm
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Intraductal papilloma of breast
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Intraductal proliferative breast lesion
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    0 / 825 (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
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Invasive ductal breast carcinoma
         subjects affected / exposed
    5 / 825 (0.61%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine benign neoplasm
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lip and/or oral cavity cancer
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    2 / 825 (0.24%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Lymphoma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Metastases to bone
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Metastases to central nervous system
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Metastases to skin
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Neoplasm malignant
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Oral papilloma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 825 (0.12%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Phaeochromocytoma
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (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
    Plasma cell myeloma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleomorphic adenoma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    5 / 825 (0.61%)
    4 / 827 (0.48%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Prostate cancer recurrent
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer stage II
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (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
    Thyroid cancer
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyosarcoma
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    PNEUMONIA METASTASIS OF OESOPHAGEAL CANCER
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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 stenosis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Arterial occlusive disease
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Arteriosclerosis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Hypertension
         subjects affected / exposed
    2 / 825 (0.24%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Hypotension
         subjects affected / exposed
    2 / 825 (0.24%)
    3 / 827 (0.36%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Shock haemorrhagic
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Liver transplant
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Physiotherapy
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff repair
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Hiatus hernia
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Adverse drug reaction
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 825 (0.24%)
    2 / 827 (0.24%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast complication associated with device
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Calcinosis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    5 / 825 (0.61%)
    8 / 827 (0.97%)
    6 / 825 (0.73%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device deployment issue
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Device dislocation
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Disease progression
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Dysplasia
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mass
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 825 (0.36%)
    7 / 827 (0.85%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    0 / 825 (0.00%)
    3 / 827 (0.36%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (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
    Vascular stent occlusion
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Drug hypersensitivity
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    4 / 825 (0.48%)
    4 / 827 (0.48%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    3 / 825 (0.36%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast haematoma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Endometrial thickening
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Menorrhagia
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Metrorrhagia
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic congestion
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Pelvic pain
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic prolapse
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Rectocele
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Uterine polyp
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Uterine prolapse
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Uterovaginal prolapse
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 825 (0.12%)
    5 / 827 (0.60%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma-chronic obstructive pulmonary disease overlap syndrome
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Bronchopneumopathy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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 obstructive pulmonary disease
         subjects affected / exposed
    5 / 825 (0.61%)
    3 / 827 (0.36%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 825 (0.36%)
    5 / 827 (0.60%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Epistaxis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Haemothorax
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Hypoxia
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Interstitial lung disease
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngeal polyp
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Organising pneumonia
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Pleural effusion
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Pneumonia aspiration
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Pulmonary embolism
         subjects affected / exposed
    3 / 825 (0.36%)
    1 / 827 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Pulmonary hilum mass
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Pulmonary oedema
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Respiratory distress
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder with depressed mood
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Bipolar I disorder
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Completed suicide
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    Confusional state
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    3 / 825 (0.36%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Panic disorder
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Psychogenic seizure
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychogenic tremor
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rapid eye movements sleep abnormal
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Suicidal ideation
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANXIETY-DEPRESSIVE DISORDER
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Bile duct obstruction
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Bile duct stone
         subjects affected / exposed
    3 / 825 (0.36%)
    3 / 827 (0.36%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary tract disorder
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Biloma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Cholangitis
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (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
    Cholangitis acute
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
         subjects affected / exposed
    2 / 825 (0.24%)
    4 / 827 (0.48%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 825 (0.24%)
    9 / 827 (1.09%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 825 (0.12%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    4 / 825 (0.48%)
    8 / 827 (0.97%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Cholestatic liver injury
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Chronic hepatic failure
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Drug-induced liver injury
         subjects affected / exposed
    0 / 825 (0.00%)
    3 / 827 (0.36%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder perforation
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Gallbladder polyp
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Hepatic haematoma
         subjects affected / exposed
    3 / 825 (0.36%)
    2 / 827 (0.24%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic lesion
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    0 / 825 (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
    Hepatitis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 825 (0.12%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperplastic cholecystopathy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Investigations
    Arthroscopy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronavirus test positive
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Fibrin D dimer increased
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Human rhinovirus test positive
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Liver function test abnormal
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Red blood cell sedimentation rate increased
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Transaminases increased
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Troponin increased
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Weight increased
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Alcohol poisoning
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaesthetic complication pulmonary
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    3 / 827 (0.36%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Concussion
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 825 (0.36%)
    3 / 827 (0.36%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Femur fracture
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Foot fracture
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated incisional hernia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Incisional hernia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Intentional overdose
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Joint injury
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Laceration
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Near drowning
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Overdose
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    0 / 825 (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
    Patella fracture
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    0 / 825 (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
    Pelvic fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Pharyngeal injury
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Post procedural complication
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural discomfort
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    5 / 825 (0.61%)
    3 / 827 (0.36%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 825 (0.12%)
    4 / 827 (0.48%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Procedural intestinal perforation
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Procedural pain
         subjects affected / exposed
    4 / 825 (0.48%)
    6 / 827 (0.73%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 825 (0.12%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Shunt malfunction
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin graft failure
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Spinal compression fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Spinal cord injury cervical
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Subdural haematoma
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    0 / 825 (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
    Tendon rupture
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Tibia fracture
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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 limb fracture
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention postoperative
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    INTRACRANIAL HEMORRHAGE
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Congenital, familial and genetic disorders
    Arnold-Chiari malformation
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Arteriovenous malformation
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Congenital cerebrovascular anomaly
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rathke's cleft cyst
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    4 / 825 (0.48%)
    7 / 827 (0.85%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    4 / 825 (0.48%)
    6 / 827 (0.73%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 825 (0.24%)
    2 / 827 (0.24%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    8 / 825 (0.97%)
    5 / 827 (0.60%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Atrioventricular block
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 825 (0.12%)
    2 / 827 (0.24%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Cardio-respiratory distress
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Cor pulmonale
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Coronary artery disease
         subjects affected / exposed
    5 / 825 (0.61%)
    4 / 827 (0.48%)
    7 / 825 (0.85%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 4
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 825 (0.12%)
    3 / 827 (0.36%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    4 / 825 (0.48%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Pericarditis
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Sinus tachycardia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Tachycardia
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Ataxia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Autonomic nervous system imbalance
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Brain mass
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Brain stem haemorrhage
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral thrombosis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Cerebrovascular accident
         subjects affected / exposed
    1 / 825 (0.12%)
    3 / 827 (0.36%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Depressed level of consciousness
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Dizziness
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Encephalopathy
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Essential tremor
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Hemiparesis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 825 (0.12%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 825 (0.12%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Intracranial pressure increased
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 825 (0.12%)
    3 / 827 (0.36%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Lumbosacral radiculopathy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Migraine
         subjects affected / exposed
    1 / 825 (0.12%)
    4 / 827 (0.48%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Motor neurone disease
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Nerve compression
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Nervous system disorder
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Parkinsonism
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Polyneuropathy
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Presyncope
         subjects affected / exposed
    0 / 825 (0.00%)
    3 / 827 (0.36%)
    0 / 825 (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
    Sciatica
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (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
    Sensory disturbance
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal epidural haemorrhage
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Syncope
         subjects affected / exposed
    7 / 825 (0.85%)
    3 / 827 (0.36%)
    5 / 825 (0.61%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Transient global amnesia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 825 (0.12%)
    3 / 827 (0.36%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    VIIth nerve paralysis
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIth nerve paralysis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 825 (0.48%)
    2 / 827 (0.24%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Pancytopenia
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polycythaemia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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 lesion
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Ear and labyrinth disorders
    Labyrinthine fistula
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 825 (0.12%)
    2 / 827 (0.24%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Macular fibrosis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Optic ischaemic neuropathy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Retinal detachment
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Vision blurred
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    7 / 825 (0.85%)
    4 / 827 (0.48%)
    7 / 825 (0.85%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall disorder
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Apical granuloma
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendix disorder
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Ascites
         subjects affected / exposed
    2 / 825 (0.24%)
    2 / 827 (0.24%)
    0 / 825 (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
    Colitis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 825 (0.00%)
    4 / 827 (0.48%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Dyschezia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Dysphagia
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 825 (0.12%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 825 (0.36%)
    3 / 827 (0.36%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Impaired gastric emptying
         subjects affected / exposed
    0 / 825 (0.00%)
    3 / 827 (0.36%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Inguinal hernia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Intestinal obstruction
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Large intestine perforation
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (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
    Pancreatitis
         subjects affected / exposed
    4 / 825 (0.48%)
    6 / 827 (0.73%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    5 / 825 (0.61%)
    1 / 827 (0.12%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis haemorrhagic
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Portal hypertensive gastropathy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Rectal haemorrhage
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 825 (0.24%)
    5 / 827 (0.60%)
    5 / 825 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Vomiting
         subjects affected / exposed
    2 / 825 (0.24%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (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
    Decubitus ulcer
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Dermatomyositis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Diabetic foot
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hidradenitis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lichen sclerosus
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Pruritus
         subjects affected / exposed
    0 / 825 (0.00%)
    5 / 827 (0.60%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 825 (0.73%)
    13 / 827 (1.57%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 6
    3 / 14
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Bladder prolapse
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (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
    Diabetic nephropathy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Hydronephrosis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower urinary tract symptoms
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    5 / 825 (0.61%)
    5 / 827 (0.60%)
    5 / 825 (0.61%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvi-ureteric obstruction
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal aneurysm
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Ureteric obstruction
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Endocrine disorders
    Adrenal haematoma
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Goitre
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Pituitary-dependent Cushing's syndrome
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Thyroid mass
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroiditis subacute
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    3 / 825 (0.36%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone disorder
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Costochondritis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture nonunion
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Gouty arthritis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inclusion body myositis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Intervertebral disc degeneration
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    3 / 825 (0.36%)
    3 / 827 (0.36%)
    6 / 825 (0.73%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 825 (0.12%)
    3 / 827 (0.36%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Myositis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    6 / 825 (0.73%)
    8 / 827 (0.97%)
    6 / 825 (0.73%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Pain in extremity
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Rhabdomyolysis
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    3 / 825 (0.36%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Tendon calcification
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebral foraminal stenosis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal infection
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Appendicitis perforated
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Bronchiolitis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Bronchitis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 825 (0.36%)
    5 / 827 (0.60%)
    6 / 825 (0.73%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 825 (0.00%)
    3 / 827 (0.36%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Coccidioidomycosis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Corona virus infection
         subjects affected / exposed
    6 / 825 (0.73%)
    7 / 827 (0.85%)
    6 / 825 (0.73%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 825 (0.00%)
    3 / 827 (0.36%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus mononucleosis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Device related infection
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Diarrhoea infectious
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    0 / 825 (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
    Diverticulitis
         subjects affected / exposed
    3 / 825 (0.36%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis viral
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Endocarditis bacterial
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Escherichia sepsis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 825 (0.24%)
    4 / 827 (0.48%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Graft infection
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Groin abscess
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Helicobacter infection
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Histoplasmosis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Infection
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Kidney infection
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Mastoiditis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical device site joint infection
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Parotid abscess
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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 abscess
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Pharyngeal abscess
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Pneumonia
         subjects affected / exposed
    5 / 825 (0.61%)
    9 / 827 (1.09%)
    7 / 825 (0.85%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    9 / 825 (1.09%)
    10 / 827 (1.21%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Post procedural sepsis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Postoperative wound infection
         subjects affected / exposed
    2 / 825 (0.24%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Pyelonephritis
         subjects affected / exposed
    5 / 825 (0.61%)
    4 / 827 (0.48%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Salmonellosis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Sepsis
         subjects affected / exposed
    7 / 825 (0.85%)
    6 / 827 (0.73%)
    7 / 825 (0.85%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Septic encephalopathy
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Septic shock
         subjects affected / exposed
    0 / 825 (0.00%)
    3 / 827 (0.36%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Staphylococcal infection
         subjects affected / exposed
    1 / 825 (0.12%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Streptococcal sepsis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Subcutaneous abscess
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Tonsillitis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Tracheobronchitis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Urinary tract infection
         subjects affected / exposed
    3 / 825 (0.36%)
    5 / 827 (0.60%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 825 (0.24%)
    3 / 827 (0.36%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Viral pericarditis
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (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
    Vulval abscess
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (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
    Wound infection
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 825 (0.00%)
    4 / 827 (0.48%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    3 / 825 (0.36%)
    3 / 827 (0.36%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    3 / 825 (0.36%)
    2 / 827 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Failure to thrive
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 825 (0.00%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Hypercreatininaemia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Hyperglycaemia
         subjects affected / exposed
    0 / 825 (0.00%)
    2 / 827 (0.24%)
    0 / 825 (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
    Hyperkalaemia
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    0 / 825 (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
    Hypoglycaemia
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 825 (0.24%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 825 (0.00%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    1 / 825 (0.12%)
    0 / 827 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 825 (0.12%)
    1 / 827 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    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
    		 OCA 10 Milligrams (mg) OCA 25 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    801 / 825 (97.09%)
    814 / 827 (98.43%)
    782 / 825 (94.79%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    106 / 825 (12.85%)
    97 / 827 (11.73%)
    88 / 825 (10.67%)
         occurrences all number
    114
    102
    94
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    148 / 825 (17.94%)
    135 / 827 (16.32%)
    138 / 825 (16.73%)
         occurrences all number
    176
    159
    158
    Oedema peripheral
         subjects affected / exposed
    47 / 825 (5.70%)
    39 / 827 (4.72%)
    42 / 825 (5.09%)
         occurrences all number
    53
    47
    48
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    81 / 825 (9.82%)
    69 / 827 (8.34%)
    62 / 825 (7.52%)
         occurrences all number
    96
    84
    72
    Psychiatric disorders
    Depression
         subjects affected / exposed
    63 / 825 (7.64%)
    54 / 827 (6.53%)
    62 / 825 (7.52%)
         occurrences all number
    71
    60
    64
    Anxiety
         subjects affected / exposed
    45 / 825 (5.45%)
    54 / 827 (6.53%)
    42 / 825 (5.09%)
         occurrences all number
    48
    57
    45
    Insomnia
         subjects affected / exposed
    68 / 825 (8.24%)
    55 / 827 (6.65%)
    48 / 825 (5.82%)
         occurrences all number
    71
    60
    48
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    37 / 825 (4.48%)
    26 / 827 (3.14%)
    49 / 825 (5.94%)
         occurrences all number
    42
    31
    62
    Aspartate aminotransferase increased
         subjects affected / exposed
    38 / 825 (4.61%)
    27 / 827 (3.26%)
    46 / 825 (5.58%)
         occurrences all number
    40
    33
    54
    Blood cholesterol increased
         subjects affected / exposed
    53 / 825 (6.42%)
    51 / 827 (6.17%)
    32 / 825 (3.88%)
         occurrences all number
    60
    55
    33
    Blood creatinine increased
         subjects affected / exposed
    53 / 825 (6.42%)
    43 / 827 (5.20%)
    43 / 825 (5.21%)
         occurrences all number
    83
    60
    58
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    28 / 825 (3.39%)
    14 / 827 (1.69%)
    43 / 825 (5.21%)
         occurrences all number
    37
    18
    49
    Glycosylated haemoglobin increased
         subjects affected / exposed
    47 / 825 (5.70%)
    40 / 827 (4.84%)
    37 / 825 (4.48%)
         occurrences all number
    50
    48
    43
    Low density lipoprotein increased
         subjects affected / exposed
    175 / 825 (21.21%)
    183 / 827 (22.13%)
    92 / 825 (11.15%)
         occurrences all number
    201
    207
    107
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    45 / 825 (5.45%)
    33 / 827 (3.99%)
    44 / 825 (5.33%)
         occurrences all number
    57
    37
    55
    Procedural pain
         subjects affected / exposed
    58 / 825 (7.03%)
    50 / 827 (6.05%)
    44 / 825 (5.33%)
         occurrences all number
    64
    58
    58
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    62 / 825 (7.52%)
    53 / 827 (6.41%)
    55 / 825 (6.67%)
         occurrences all number
    67
    59
    71
    Headache
         subjects affected / exposed
    83 / 825 (10.06%)
    87 / 827 (10.52%)
    90 / 825 (10.91%)
         occurrences all number
    108
    97
    116
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    59 / 825 (7.15%)
    57 / 827 (6.89%)
    48 / 825 (5.82%)
         occurrences all number
    66
    66
    51
    Abdominal pain
         subjects affected / exposed
    139 / 825 (16.85%)
    135 / 827 (16.32%)
    132 / 825 (16.00%)
         occurrences all number
    178
    173
    172
    Abdominal pain upper
         subjects affected / exposed
    95 / 825 (11.52%)
    104 / 827 (12.58%)
    106 / 825 (12.85%)
         occurrences all number
    112
    135
    129
    Constipation
         subjects affected / exposed
    115 / 825 (13.94%)
    128 / 827 (15.48%)
    92 / 825 (11.15%)
         occurrences all number
    128
    146
    99
    Diarrhoea
         subjects affected / exposed
    112 / 825 (13.58%)
    108 / 827 (13.06%)
    145 / 825 (17.58%)
         occurrences all number
    145
    146
    205
    Dyspepsia
         subjects affected / exposed
    48 / 825 (5.82%)
    35 / 827 (4.23%)
    41 / 825 (4.97%)
         occurrences all number
    58
    38
    52
    Gastrooesophageal reflux disease
         subjects affected / exposed
    51 / 825 (6.18%)
    63 / 827 (7.62%)
    47 / 825 (5.70%)
         occurrences all number
    55
    70
    51
    Nausea
         subjects affected / exposed
    148 / 825 (17.94%)
    165 / 827 (19.95%)
    150 / 825 (18.18%)
         occurrences all number
    211
    211
    187
    Vomiting
         subjects affected / exposed
    71 / 825 (8.61%)
    90 / 827 (10.88%)
    66 / 825 (8.00%)
         occurrences all number
    92
    115
    81
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    50 / 825 (6.06%)
    66 / 827 (7.98%)
    30 / 825 (3.64%)
         occurrences all number
    55
    72
    36
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    294 / 825 (35.64%)
    470 / 827 (56.83%)
    210 / 825 (25.45%)
         occurrences all number
    429
    907
    286
    Pruritus generalised
         subjects affected / exposed
    15 / 825 (1.82%)
    55 / 827 (6.65%)
    13 / 825 (1.58%)
         occurrences all number
    16
    79
    14
    Rash
         subjects affected / exposed
    46 / 825 (5.58%)
    61 / 827 (7.38%)
    48 / 825 (5.82%)
         occurrences all number
    59
    68
    59
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    117 / 825 (14.18%)
    132 / 827 (15.96%)
    134 / 825 (16.24%)
         occurrences all number
    143
    154
    161
    Back pain
         subjects affected / exposed
    136 / 825 (16.48%)
    105 / 827 (12.70%)
    120 / 825 (14.55%)
         occurrences all number
    159
    121
    155
    Muscle spasms
         subjects affected / exposed
    47 / 825 (5.70%)
    49 / 827 (5.93%)
    60 / 825 (7.27%)
         occurrences all number
    53
    58
    73
    Musculoskeletal pain
         subjects affected / exposed
    65 / 825 (7.88%)
    53 / 827 (6.41%)
    61 / 825 (7.39%)
         occurrences all number
    78
    64
    65
    Pain in extremity
         subjects affected / exposed
    67 / 825 (8.12%)
    67 / 827 (8.10%)
    66 / 825 (8.00%)
         occurrences all number
    76
    78
    75
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    81 / 825 (9.82%)
    66 / 827 (7.98%)
    66 / 825 (8.00%)
         occurrences all number
    107
    80
    83
    Influenza
         subjects affected / exposed
    61 / 825 (7.39%)
    63 / 827 (7.62%)
    59 / 825 (7.15%)
         occurrences all number
    66
    69
    66
    Nasopharyngitis
         subjects affected / exposed
    82 / 825 (9.94%)
    80 / 827 (9.67%)
    70 / 825 (8.48%)
         occurrences all number
    113
    105
    103
    Sinusitis
         subjects affected / exposed
    74 / 825 (8.97%)
    73 / 827 (8.83%)
    80 / 825 (9.70%)
         occurrences all number
    93
    113
    130
    Upper respiratory tract infection
         subjects affected / exposed
    88 / 825 (10.67%)
    103 / 827 (12.45%)
    84 / 825 (10.18%)
         occurrences all number
    117
    131
    108
    Urinary tract infection
         subjects affected / exposed
    147 / 825 (17.82%)
    151 / 827 (18.26%)
    133 / 825 (16.12%)
         occurrences all number
    229
    239
    210
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    112 / 825 (13.58%)
    99 / 827 (11.97%)
    94 / 825 (11.39%)
         occurrences all number
    134
    120
    111
    Hypercholesterolaemia
         subjects affected / exposed
    57 / 825 (6.91%)
    48 / 827 (5.80%)
    26 / 825 (3.15%)
         occurrences all number
    60
    51
    30
    Hyperlipidaemia
         subjects affected / exposed
    80 / 825 (9.70%)
    90 / 827 (10.88%)
    33 / 825 (4.00%)
         occurrences all number
    84
    97
    33
    Type 2 diabetes mellitus
         subjects affected / exposed
    70 / 825 (8.48%)
    47 / 827 (5.68%)
    60 / 825 (7.27%)
         occurrences all number
    72
    50
    61

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Sep 2015
    Amended to incorporate feedback received from regulatory authorities (RA) and to clarify various aspects of the study design. Protocol V2 was published internally at ICPT but was not submitted to any RAs, Ethics Committees (ECs) or sites. Instead Protocol V3 dated 30Sep2015 was released to RAs, ECs and sites. Changes to the assessments, such as more frequent hepatocellular carcinoma screenings, were implemented to expedite identification of potential liver-related clinical outcomes. In addition, minor formatting and editorial changes were done (not listed in the summary of changes table).
    30 Sep 2015
    Amended to add definitions from Chapters 8 through 10 of “Standardized Definitions for Cardiovascular and Stroke Endpoint Events in Clinical Trials,” dated August 20, 2014 to Appendix D. Additionally, the protocol was edited to clarify that subjects will be required to participate in noninvasive radiological liver fibrosis measurements at selected centers where the devices are available.
    17 Dec 2015
    Sweden: Amended to add clarifying information showing that OCA may increase the exposure of narrow therapeutic index drugs that are substrates for CYP1A2, to answer questions raised by regulatory authorities
    21 Dec 2015
    France: Amended to exclude subjects with acute cholecystitis or a biliary obstruction and to clarify that bile acid sequestrants include colestyramine and its derivatives colestipol, colesevelam or other sequestrants.
    08 Apr 2016
    Switzerland Addendum 1: Created to clarify the contraception use as designated inclusion criteria 6 at the request of the Swiss ECs. (Format of this was a memo to Investigators and other relevant parties in Switzerland, signed by CH general manager as the sponsor representative and by PIs in CH as agree to conduct as per this addendum)
    14 Apr 2016
    Amended to add: - Chronic Liver Disease Questionnaire - NAFLD and the Work Productivity and Activity Index to further assess health-related quality of life - Multi-parametric magnetic resonance imaging to the list of non-invasive radiological measurements of liver fibrosis. - Expanded the list of conjugates or metabolites of OCA for assessment to include OCA glucuronide. - A list of events that are disease-related and exempt from expeditious regulatory reporting was added so that unblinding of a SUSAR that is also a clinical outcomes event would not disqualify the event from adjudication. - The requirement for subjects to not take or be on a stable dose of drugs with potential NASH-modifying properties for 6 months before Day 1 was limited to subjects providing historical biopsies to determine study eligibility. - Specific restrictions for diabetes and weight loss pharmacotherapies were removed as was the requirement for allowed concomitant medications and supplements to be stable for 30 days before Day 1. - Additionally, various aspects of study design and study population were clarified - Feedback from Swedish & French regulatory agencies was incorporated. (Protocol v3.1 & 3.2)
    18 May 2016
    EU Countries: Section 2 (Synopsis) was revised to add the full list of bullets for exclusion criteria 4 that are listed in section 8.1.2 (subject exclusion criteria)
    14 Nov 2016
    Amended to change the number of central pathologists needed to determine histological presence of NASH for study eligibility from 2 to 1 Rationale: For Version 4 of the protocol, the histology evaluation procedure at Screening for eligibility required that slides from subjects deemed eligible for participation by the initial pathologist to be sent to a second pathologist for confirmation of eligibility. Given that the second confirmatory reading was generally concordant with the first for the subjects evaluated thus far, only 1 pathologist will now be required to determine study eligibility. - Add option for subjects who successfully complete the EOT/EOS Visit upon closing of the Study 747-303 to receive open-label OCA for up to 5 years in an extension study. - Additionally, various aspects of the study design and study population were clarified.
    30 Mar 2017
    Denmark Addendum 1: Removes all reference made to the 5-year open label extension study
    19 Sep 2017
    Safety Amendment: Protocol version 5.0 was amended to address the evolution of the clinical research of NASH and discussions with the US FDA. This appendix summarizes changes made to the protocol per Safety Amendment dated 19 Sep 2017. Additional changes clarifying the objectives, interim and final analyses, and modifications of assessments and procedures are summarized in Appendix J. The Safety Amendment dated was prepared in consultation with the FDA to develop procedures to closely monitor subjects and ensure early identification of potential decompensation and/or liver injury. The amendment proposed more extensive safety monitoring procedures and appropriate dosing adjustments, interruptions, and discontinuations to improve subject oversight and safety including: • Educating the Investigators and subjects about the signs and symptoms of potential hepatic injury and progression to cirrhosis and/or decompensation and the importance of appropriate follow-up and dose adjustments. Key components of safety monitoring and dose adjustment procedures include: - Telephone contact every 2 weeks to: - Review the signs and symptoms of potential hepatic injury and decompensation - Determine if the subject had any recent interaction with other health care professionals (HCPs) - Laboratory assessments every 6 weeks to review specific biochemical triggers and clinical criteria for monitoring potential hepatic injury or decompensation - Criteria for interruption or discontinuation of investigational product, as well as rules for possible re-challenge and dose adjustments in the event of: - Hepatic injury - Progression to cirrhosis and/or decompensation Criteria for close observation of subjects with suspected hepatic injury or progression to cirrhosis or decompensation
    02 Oct 2017
    The Introduction was revised to highlight the need for close monitoring specifically in patients with clinical evidence of hepatic decompensation and other complications due to progression of disease. The primary objective assessed at Month 18 was revised to replace the analysis of the coprimary endpoints with the analysis of multiple primary endpoints. Definition of NASH resolution clarified. Exploratory objective assessed at Month 18 was revised to include morphometric assessment of histology sections for only collagen and not fat. The study design was modified to increase enrolment to approximately 2085 subjects with biopsy-confirmed stage 2 or stage 3 liver fibrosis. An additional cohort of approximately 285 subjects with stage 1 fibrosis with at least 1 accompanying comorbidity will be enrolled to gather information on the safety of OCA and progression of liver disease in this population. The study design was also modified to increase accrual from 1 year to a 2year period. The study design and determination of sample size sections describe changes in the interim analysis sample size to reflect the revised powering assumptions for the interim analysis of primary endpoints and the increased accrual period. A description of procedures to assess progression of liver disease was added. Guidance for management of disease progression was added including procedures for dose adjustment for subjects who have disease progression and procedures for interruption and discontinuation of investigational product for safety were added. Procedures were added for collecting blood samples to determine the PK of OCA and its metabolites in subjects with disease progression. Guidance was added that subjects and investigators should be instructed to contact the site and Medical Monitor, respectively upon awareness of development in signs and symptoms of potential hepatic decompensation. Guidance added to monitor amylase and lipase levels in subjects with suspected acute pancreatitis.
    17 Nov 2017
    Switzerland Addendum 2: Country specific protocol addendum to clarify the contraception use as designated in Inclusion criteria 6 and associated text in the protocol for subjects enrolled at sites in Switzerland. Updated to be consistent with the contraception expectations required by CH regulatory authorities.
    02 Jan 2018
    Addendum 1 Country Specific US: Amended to incorporate Month 2 visit for subjects enrolled at sites in USA to comply with FDA request to perform monthly physical exams and labs for the 1st 3 months
    11 Apr 2018
    Information added to clarify secondary and exploratory objectives, revised secondary objectives order. Clarified changes in fibrosis and included effects on liver biochemistry and measures of liver function as secondary analysis to support efficacy. Safety amendment assessments of telephone contacts every 2 weeks and laboratory visits every 6 weeks were removed. New information added on summary of known potential risks of OCA. Information added to clarify monitoring and assessment of subjects who may be at risk for suspected hepatic injury or decompensation, by providing specific guidance to investigators to educate subjects, monitor subjects for signs and symptoms of suspected hepatic injury or decompensation as well as criteria for study drug interruption or discontinuation. Instructions included to discontinue IP and obtain a liver biopsy in subjects who undergo bariatric surgery during study. Guidance added to inform Investigator to notify the Medical Monitor when deciding to discontinue IP. The windows for Month 18 and Month 48 visits are expanded. The –6-week limit is more reflective of way data points are assigned to visits for analyses, but upper limit was kept at +2 to expedite data collection and lock. Month 48 visit window expanded (8 weeks) to +/- 4 weeks to allow scheduling of biopsies. Exploratory assessments reduced or streamlined to reduce subject burden including: Stopping collection of blood samples for future analyses and genetic analyses. Limit assessments of noninvasive serum and radiological assessments of fibrosis to a subset of subjects. Assessment of stool samples for microbiome is being limited to those subjects who provided baseline samples only and will not be collected from newly enrolled. Revisions provided to clarify statistical analyses of primary, secondary, and exploratory endpoints. Appendix B revised to provide guidance to Investigators to educate subjects and evaluate signs and symptoms of hepatic injury and decompensation.
    01 May 2018
    US Addendum 1 Admin Letter: Updated the contact info for the medical monitor. Addendum 1 Clarification letter: Clarification of addendum 1: 2Jan2018 for US – that a Physical Examination will be performed for new subjects at Months 1, 2 & 3.
    08 Jan 2019
    Protocol 747-303 has been updated to version 8 to include the following key changes: - Information was added for the implementation of the new requirements for IP interruption and medical management procedures for subjects with symptomatic cholelithiasis and/or cholecystitis. - A number of updates were made to the statistical section of the protocol based on interactions with Health Authorities. - Hepatocellular carcinoma (HCC) was removed from primary composite endpoint based on recommendations from Health Authorities.
    09 Jul 2019
    Amended to include the following information: 1) Month 18 biopsy removed 2) ARFI removed as an assessment 3) 10-year ASCVD Risk added as an assessment 4) Additional strategies and procedures for subject retention
    02 Oct 2019
    Admin Letter to Prot V9.0: To explain the error in the synopsis regarding the diagram of the study timeline.
    03 Feb 2020
    Amended to include the following information: 1) DMC recommendation for treatment-emergent acute or nonacute pancreatitis 2) Liver biopsy for suspected progression to cirrhosis 3) Highly effective contraception language per CTFG guidance 4) SUSAR definition per ICH guidance
    01 May 2020
    The restrictions that have recently been imposed to contain the global COVID-19 pandemic, such as social distancing measures, stay at home orders, and other limitations have impeded the ability of subjects and site staff to complete protocol-specified procedures. Some study sites are not able to perform protocol-specified procedures and assessments. In addition, some subjects are unable to return to study sites for evaluations and/or to receive continued supply of investigational product (IP). The purpose of this Country-Specific Protocol Addendum is to describe the requirements and processes under which subjects who are unable to return to study sites may complete protocol specified assessments and continue to receive investigational product until in-person site visits can resume. In an effort to minimize the potential adverse impact of restrictions from the COVID-19 pandemic on achieving the objectives of the study, while continuing to ensure the safety of participating subjects, the following approaches will apply to the study protocol, effective immediately.
    04 May 2021
    1) Update to the end-of-study primary objective for progression of cirrhosis to include all clinical evidence beyond only histological changes 2) Inclusion of Hepatic Safety Adjudication Committee and Renal Adjudication Committee for the adjudication of all events of potential hepatic injury and acute kidney injury, respectively. The protocol was updated to ensure these events will be provided to the DMC for inclusion in their review as well as added to the Safety Objectives to be assessed at the End of Study. 3) Updated process for the monitoring and management of potential DILI and updated the DILI algorithm and laboratory triggers to monitor hepatic injury 4) Clarification of language on PK sample collection following investigational product interruption or discontinuation due to suspected hepatic injury and progression to cirrhosis, within 7 days of experiencing a serious adverse event, and at the time of liver biopsy. Additional PK sparse sample collection was added to each study visit after Month 18 to adequately capture the OCA exposure-response relationships for efficacy and safety 5) Additional sections added to address monitoring and management of renal impairment and nephrolithiasis, hyperglycemia, and dyslipidemia. Additional education and assessments to identify intercurrent illness and/or potential adverse events was added to each study visit after Month 18. 6) Inclusion of local laboratory results and reference ranges into the eCRF and inclusion local pathology reports into the eCRF 7) COVID-19 related changes to the protocol 8) The use of “suspected” was globally updated to “potential” throughout the protocol 9) Study duration was updated from 7 to 10 years based on current estimates for outcome accrual 10) Previous Summary of Changes for each protocol amendment removed. Moving forward, only the current Summary of Changes will be included.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Nov 2023
    On 22 Jun 2023, Intercept received a Complete Response Letter (CRL) from the FDA stating that the new drug application (NDA) could not be approved in its present form. Based on the content of the CRL, any resubmission of an NDA for OCA in NASH would require, at a minimum, successful completion of the long-term outcomes phase of the REGENERATE study. The 747-303 study was terminated with only critical data fields cleaned which consisted of all deaths, hepatic serious adverse events (SAEs), all adjudicated Month 48 biopsies collected through 30 Jun 2023, end of treatment/end of study (EOS) status for all subjects, and medication exposure.
    -

    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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