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    Clinical Trial Results:
    A Phase 3 Multicenter, Open-Label Study to Evaluate the Safety of Daily Oral Dosing of Tafamidis Meglumine (PF-06291826-83) 20 mg or 80 mg [or Tafamidis (PF-06291826-00) 61 mg] in Subjects Diagnosed With Transthyretin Cardiomyopathy (ATTR-CM)

    Summary
    EudraCT number
    		 2016-000868-42
    Trial protocol
    		 ES   BE   CZ   DE   SE   NL   GB   IT  
    Global end of trial date
    02 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Nov 2024
    First version publication date
    07 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B3461045
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02791230
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street,, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    02 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to obtain additional, long-term, safety data for tafamidis in subjects with transthyretin amyloid cardiomyopathy (ATTR-CM) and to provide investigational product, tafamidis, to enrolled subjects until local availability by prescription for the ATTR-CM indication.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 20
    Country: Number of subjects enrolled
    United States: 819
    Country: Number of subjects enrolled
    Belgium: 35
    Country: Number of subjects enrolled
    Czechia: 56
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Spain: 187
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    French Southern Territories: 206
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    Australia: 77
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Canada: 191
    Country: Number of subjects enrolled
    Japan: 35
    Worldwide total number of subjects
    1728
    EEA total number of subjects
    351
    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)
    121
    From 65 to 84 years
    1374
    85 years and over
    233

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study consisted of two cohorts: Cohort A & B. Cohort A: Participants diagnosed with ATTR-CM who completed 30 months of participation in parent study [B3461028 (NCT01994889)] were enrolled in this extension study B3461045.Cohort B: Participants diagnosed with ATTR-CM who did not participate in parent study were enrolled in this extension study.

    Pre-assignment
    Screening details
    		 A total of 1733 participants were enrolled in this current extension study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A: Tafamidis (Parent and Extension Study)
    Arm description
    		 Participants who received tafamidis 20 milligram (mg) or 80 mg orally once daily in the parent study for 30 months (complete participation), after enrollment in the current extension study, continued to receive the same dose and later switched to tafamidis 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), orally once daily along with standard of care for up to 60 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tafamidis meglumine
    Investigational medicinal product code
    PF-06291826
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tafamidis 20mg or 80 mg (4 capsules of 20 mg each), and later switched to 61 mg capsule (where available) orally once daily for 60 months.

    Arm title
    		 Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study)
    Arm description
    		 Participants who received placebo orally once daily in the parent study for 30 months (complete participation), after enrollment in the current extension study, received tafamidis 20 mg or 80 mg and later switched to tafamidis 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), orally once daily along with standard of care for up to 60 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tafamidis meglumine
    Investigational medicinal product code
    PF-06291826
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tafamidis 20 mg or 80 mg (4 capsules of 20 mg each), and later switched to 61 mg capsule (where available) orally once daily for 60 months.

    Arm title
    		 Cohort B: Tafamidis (Only in extension study)
    Arm description
    		 Participants who did not participate in the parent study and received tafamidis at a dose of 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), once daily along with standard of care for up to 60 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tafamidis meglumine
    Investigational medicinal product code
    PF-06291826
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tafamidis 61 mg capsule where available (or 80 mg (4 capsules of 20 mg each)), orally once daily for 60 months.

    Number of subjects in period 1
    		Cohort A: Tafamidis (Parent and Extension Study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study) Cohort B: Tafamidis (Only in extension study)
    Started
    170
    82
    1476
    Completed
    84
    31
    988
    Not completed
    86
    51
    488
         Consent withdrawn by subject
    24
    13
    172
         Adverse Event
    10
    9
    66
         Failure to Meet Randomization Criteria
    3
    2
    15
         Death
    38
    25
    184
         Study sites terminated by sponsor
    1
    -
    5
         Unspecified
    9
    1
    28
         Medication Error Without Associated Adverse Event
    -
    1
    1
         Lost to follow-up
    -
    -
    10
         Lack of efficacy
    1
    -
    3
         Protocol deviation
    -
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: Tafamidis (Parent and Extension Study)
    Reporting group description
    		 Participants who received tafamidis 20 milligram (mg) or 80 mg orally once daily in the parent study for 30 months (complete participation), after enrollment in the current extension study, continued to receive the same dose and later switched to tafamidis 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), orally once daily along with standard of care for up to 60 months.

    Reporting group title
    Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study)
    Reporting group description
    		 Participants who received placebo orally once daily in the parent study for 30 months (complete participation), after enrollment in the current extension study, received tafamidis 20 mg or 80 mg and later switched to tafamidis 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), orally once daily along with standard of care for up to 60 months.

    Reporting group title
    Cohort B: Tafamidis (Only in extension study)
    Reporting group description
    		 Participants who did not participate in the parent study and received tafamidis at a dose of 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), once daily along with standard of care for up to 60 months.

    Reporting group values
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study) Cohort B: Tafamidis (Only in extension study) Total
    Number of subjects
    		 170 82 1476 1728
    Age categorical
    Units: Participants
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 9 6 106 121
        From 65-84 years
    		 142 72 1160 1374
        85 years and over
    		 19 4 210 233
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 76.73 ( 6.75 ) 76.41 ( 6.47 ) 76.51 ( 7.75 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 13 8 165 186
        Male
    		 157 74 1311 1542
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 9 5 66 80
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 15 5 139 159
        White
    		 144 72 1252 1468
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 2 0 19 21
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 1 37 43
        Not Hispanic or Latino
    		 164 81 1433 1678
        Unknown or Not Reported
    		 1 0 6 7

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: Tafamidis (Parent and Extension Study)
    Reporting group description
    		 Participants who received tafamidis 20 milligram (mg) or 80 mg orally once daily in the parent study for 30 months (complete participation), after enrollment in the current extension study, continued to receive the same dose and later switched to tafamidis 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), orally once daily along with standard of care for up to 60 months.

    Reporting group title
    Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study)
    Reporting group description
    		 Participants who received placebo orally once daily in the parent study for 30 months (complete participation), after enrollment in the current extension study, received tafamidis 20 mg or 80 mg and later switched to tafamidis 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), orally once daily along with standard of care for up to 60 months.

    Reporting group title
    Cohort B: Tafamidis (Only in extension study)
    Reporting group description
    		 Participants who did not participate in the parent study and received tafamidis at a dose of 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), once daily along with standard of care for up to 60 months.

    Subject analysis set title
    Cohort A: Tafamidis(Parent study) & Tafamidis(Extension Study)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants who received tafamidis 20 mg or 80 mg orally once daily in the parent study for 30 months (complete participation) and after enrollment in the current extension study, continued to receive the same dose and later switched to tafamidis 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), orally once daily along with standard of care for up to 60 months.

    Subject analysis set title
    Cohort A: Placebo (Parent Study) & Tafamidis (Extension Study)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants who received placebo orally once daily in the parent study for 30 months (complete participation) and after enrollment in the current extension study, received tafamidis 20 mg or 80 mg and later switched to tafamidis 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), orally once daily along with standard of care for up to 60 months.

    Primary: Time to All-Cause Mortality: Cohort A

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    End point title
    		 Time to All-Cause Mortality: Cohort A
    End point description
    Time to all-cause mortality was calculated from first dose of randomized treatment in parent study (PS) B3461028 to all-cause mortality events which included death,heart transplants&cardiac mechanical assist device implantation treated as death.Treated participants from PS who discontinued before this study were included as planned.Data from participants who dropped out for liver-only transplantation were handled like all censored participants.Censored participants were participants completed or discontinued from study,were alive at analysis.Combined mortality analysis(CMA)set included all participants in Intent-To-Treat (ITT)analysis set from study B3461028.Mortality analyses in B3461045 for Cohort A included combined data from participants in B3461028,including participants who died,discontinued in B3461028,or were not enrolled into B3461045(i.e. ITT Analysis Set from B3461028)with mortality data through participation in B3461045.Analysis was based on pooled dose groups,as per SAP.
    End point type
    Primary
    End point timeframe
    From first dose of randomized treatment in parent study (B3461028) up to 28 days post last dose of study treatment in current extension study (B3461045), [approximately up to 91 months]
    End point values
    		 Cohort A: Tafamidis(Parent study) & Tafamidis(Extension Study) Cohort A: Placebo (Parent Study) & Tafamidis (Extension Study)
    Number of subjects analysed
    264
    177
    Units: Months
        median (confidence interval 95%)
    58.7 (50.3 to 68.4)
    35.8 (29.7 to 41.1)
    Statistical analysis title
    		 Tafamidis PS & ES vs Placebo PS & Tafamidis ES
    Comparison groups
    Cohort A: Tafamidis(Parent study) & Tafamidis(Extension Study) v Cohort A: Placebo (Parent Study) & Tafamidis (Extension Study)
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6202
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4865
         upper limit
    		 0.7906

    Primary: Number of Participants With All-Cause Mortality Events: Cohort B

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    End point title
    		 Number of Participants With All-Cause Mortality Events: Cohort B [1] [2]
    End point description
    All cause mortality included all participants who had discontinue for transplantation (i.e, heart transplantation and combined heart and liver transplantation) or for implantation of a cardiac mechanical assist device, were handled in the same manner as death. Data from participants who dropped out for a liver-only transplantation were handled in the same manner as the data from all other censored participants. Censored participants were participants who completed study or discontinued from the study (including discontinued by sponsor or participants withdrew, or discontinued due to AE), or alive at the time of analysis. Safety analysis population consisted of all participants (Cohort B) who were enrolled in this study and who had taken at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    B3461045: From first dose of treatment up to 28 days post last dose of study treatment (approximately up to 61 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses was planned for this primary end point
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is reporting statistics for the arms specified
    End point values
    		 Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    1476
    Units: Participants
    345
    No statistical analyses for this end point

    Primary: Number of Participants With Treatment-Emergent Adverse Events (AEs)

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (AEs) [3]
    End point description
    An AEs was any untoward medical occurrence who received investigational product or medical device; the event need not necessarily have causal relationship with treatment or usage.Treatment emergent AE was defined as an event that emerged during treatment period that was absent before treatment or worsened during the treatment period relative to pretreatment state. AEs included both SAEs and all Non-SAEs. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death;was life-threatening(immediate risk of death);required inpatient hospitalization or prolongation of existing hospitalization;resulted in persistent or significant disability/incapacity;resulted in congenital anomaly/birth defect;considered an important medical event.Safety analysis population consisted of all participants (Cohorts A&B) who were enrolled in this study & taken at least 1 dose of study medication.This analysis (cohort A) was based on pooled dose groups, as per the SAP.
    End point type
    Primary
    End point timeframe
    B3461045: From first dose of treatment up to 28 days post last dose of study treatment (approximately up to 61 months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses was planned for this primary end point
    End point values
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study) Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    170
    82
    1476
    Units: Participants
    168
    79
    1294
    No statistical analyses for this end point

    Other pre-specified: Time to Cardiovascular-Related Mortality Events: Cohort A

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    End point title
    		 Time to Cardiovascular-Related Mortality Events: Cohort A
    End point description
    Time to cardiovascular-related mortality was calculated from first dose of randomized treatment in B3461028.Participants who discontinued for transplantation (that is heart transplantation and combined heart and liver transplantation) or for implantation of cardiac mechanical assist device were treated as a death.Treated participants from the parent study who discontinued prior to the start of this study were also included in this analysis as planned. Kaplan-Meier method was used. CMA set included all participants in the ITT analysis set from study B3461028 (NCT01994889). Mortality analyses in study B3461045 for Cohort A participants were combined data from participants in study B3461028 (NCT01994889), including participants who died, discontinued in B3461028, or were not enrolled into B3461045 (i.e. ITT Analysis Set from B3461028 [NCT01994889]) with mortality data through participation in the B3461045 study. This analysis was based on the pooled dose groups, as per the SAP.
    End point type
    Other pre-specified
    End point timeframe
    From first dose of randomized treatment in parent study (B3461028) up to 28 days post last dose of study treatment in current extension study (B3461045), [approximately up to 91 months]
    End point values
    		 Cohort A: Tafamidis(Parent study) & Tafamidis(Extension Study) Cohort A: Placebo (Parent Study) & Tafamidis (Extension Study)
    Number of subjects analysed
    264
    177
    Units: Months
        median (confidence interval 95%)
    70.2 (63.4 to 88.8)
    40.8 (34.1 to 50.7)
    Statistical analysis title
    		 Tafamidis PS & ES vs Placebo PS & Tafamidis ES
    Comparison groups
    Cohort A: Tafamidis(Parent study) & Tafamidis(Extension Study) v Cohort A: Placebo (Parent Study) & Tafamidis (Extension Study)
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005
    Method
    		 Cox Proportional Hazards model
    Parameter type
    		 Hazard ratio
    Point estimate
    0.6133
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4666
         upper limit
    		 0.8062

    Other pre-specified: Number of Participants With Cardiovascular Related Mortality Events: Cohort B

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    End point title
    		 Number of Participants With Cardiovascular Related Mortality Events: Cohort B [4]
    End point description
    Deaths adjudicated as cardiovascular-related and indeterminate were reported. Cardiovascular-related mortality events included deaths, heart transplants and cardiac mechanical assist devices implantation treated as death. Cardiovascular relatedness was based on clinical judgement. Safety analysis population included all participants who were enrolled in this study and taken at least 1 dose of study medication.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: From first dose of treatment up to 28 days post last dose of study treatment (approximately up to 61 months)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is reporting statistics for the arms specified
    End point values
    		 Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    1476
    Units: Participants
    204
    No statistical analyses for this end point

    Other pre-specified: Mean Annualized Rate of All Cause Hospitalizations

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    End point title
    		 Mean Annualized Rate of All Cause Hospitalizations
    End point description
    Annual rate of all cause hospitalization was calculated for each participant as the participant's number of all cause hospitalizations divided by this participant's duration on study in years. Hospitalization was defined as any initial admission (even less than 24 hours) in a hospital or equivalent healthcare facility or any prolongation of an existing admission. Only all cause hospitalizations where the participant was admitted to a hospital during the current extension study were included in this analysis. Any hospitalizations prior to randomization date were not included. Safety analysis population included all participants who were enrolled in this study and taken at least 1 dose of study medication. This analysis (Cohort A) was based on the pooled dose groups, as per the SAP.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: From first dose of treatment up to 28 days post last dose of study treatment (approximately up to 61 months)
    End point values
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study) Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    170
    82
    1476
    Units: Hospitalization/year
        arithmetic mean (standard deviation)
    1.67 ( 5.830 )
    1.84 ( 2.275 )
    0.96 ( 5.117 )
    No statistical analyses for this end point

    Other pre-specified: Mean Annualized Rate of Cardiovascular (CV)-Related Hospitalizations

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    End point title
    		 Mean Annualized Rate of Cardiovascular (CV)-Related Hospitalizations
    End point description
    Annual rate of CV related hospitalization was calculated for each participant as the participant's number of CV related hospitalizations divided by this participant's duration on study in years. CV-related hospitalizations included hospitalizations due to heart failure, arrhythmia, myocardial infarction, stroke, and other cardiovascular-related events. Hospitalization was defined as any initial admission (even less than 24 hours) in a hospital or equivalent healthcare facility or any prolongation of an existing admission. Admission also included transfer within the hospital to an acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a tuberculosis unit). Safety analysis population consisted of all participants (Cohorts A and B) who were enrolled in this study and taken at least 1 dose of study medication. This analysis (Cohort A) was based on the pooled dose groups, as per the SAP.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: From first dose of treatment up to 28 days post last dose of study treatment (approximately up to 61 months)
    End point values
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study) Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    170
    82
    1476
    Units: CV related hospitalization/year
        arithmetic mean (standard deviation)
    1.09 ( 5.409 )
    1.14 ( 1.899 )
    0.50 ( 1.567 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Scores at Months 12, 30, 42, 60 and 90: Cohort A

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    End point title
    		 Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Scores at Months 12, 30, 42, 60 and 90: Cohort A
    End point description
    KCCQ: 23-item,self-administered questionnaire assesses health status & health-related Quality of life (QoL) in participants with heart failure.KCCQ has 8 domains:physical limitations,symptom stability,symptom frequency,symptom burden,total symptom (mean of symptom frequency & symptom burden),self-efficacy,quality of life & social limitations).Scores were generated for each domain & scaled from 0 (worst)-100 (best possible status).KCCQ-clinical summary score=mean of domains- physical limitation & total symptoms & transformed to single score which ranged from 0 -100, higher scores =better health status. Data for change from baseline is reported as least square (LS) mean.CMA set was analyzed.All participants reported under "Number of Participants Analyzed" contributed data to table;however, may not have evaluable data for every row.“Number Analyzed (n)” =number of participants evaluable at specified time points.Therefore, this analysis was based on the pooled dose groups,as per the SAP.
    End point type
    Other pre-specified
    End point timeframe
    B3461028: Baseline (Day 1, pre-dose), Months 12, 30; B3461045: Months 42, 60 and 90 (time points were relative to Day 1 from B3461028; 42, 60 and 90 Months were 12, 30 and 60 Months of B3461045)
    End point values
    		 Cohort A: Tafamidis(Parent study) & Tafamidis(Extension Study) Cohort A: Placebo (Parent Study) & Tafamidis (Extension Study)
    Number of subjects analysed
    264
    177
    Units: Units on a scale
    least squares mean (standard error)
        Change at Month 12 (n= 221, 145)
    -3.17 ( 1.016 )
    -10.2 ( 1.316 )
        Change at Month 30 (n= 170, 84)
    -7.41 ( 1.185 )
    -19.9 ( 1.999 )
        Change at Month 42 (n= 143, 54)
    -11.2 ( 1.483 )
    -25.4 ( 2.143 )
        Change at Month 60 (n= 64, 22)
    -11.8 ( 1.756 )
    -25.1 ( 3.287 )
        Change at Month 90 (n= 9, 2)
    -17.4 ( 2.758 )
    -56.9 ( 1.868 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in KCCQ Overall Score at Months 12, 30, 42, 60, 90: Cohort A

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    End point title
    		 Change From Baseline in KCCQ Overall Score at Months 12, 30, 42, 60, 90: Cohort A
    End point description
    KCCQ: 23-item, self-administered questionnaire assesses health status & health-related QoL in participants with heart failure. KCCQ has 8 domains:physical limitations, symptom stability,symptom frequency,symptom burden,total symptom(mean of symptom frequency and symptom burden),self-efficacy, quality of life & social limitations).Scores were generated for each domain and scaled from 0 (worst)-100 (best possible status). KCCQ-overall score=mean of domains-physical limitation, total symptoms,quality of life, social limitation & transformed to single score which ranged from 0 (worst)-100 (best possible status),higher scores=better health status. Data for change from baseline reported as LS mean. CMA set was analyzed. All participants reported under "Number of Participants Analyzed" contributed data to table; may not have evaluable data for every row.“n”=number of participants evaluable at specified time points.Therefore, this analysis was based on the pooled dose groups, as per the SAP.
    End point type
    Other pre-specified
    End point timeframe
    B3461028: Baseline (Day 1, pre-dose), Months 12, 30; B3461045: Months 42, 60 and 90 (time points were relative to Day 1 from B3461028; 42, 60 and 90 Months were 12, 30 and 60 Months of B3461045)
    End point values
    		 Cohort A: Tafamidis(Parent study) & Tafamidis(Extension Study) Cohort A: Placebo (Parent Study) & Tafamidis (Extension Study)
    Number of subjects analysed
    264
    177
    Units: Units on a scale
    least squares mean (standard error)
        Change at Month 12 (n= 221, 145)
    -1.97 ( 1.131 )
    -9.69 ( 1.428 )
        Change at Month 30 (n= 170, 84)
    -6.07 ( 1.399 )
    -19.5 ( 1.908 )
        Change at Month 42 (n= 143, 54)
    -8.81 ( 1.470 )
    -24.0 ( 2.114 )
        Change at Month 60 (n= 64, 22)
    -8.56 ( 1.646 )
    -24.5 ( 3.020 )
        Change at Month 90 (n= 9, 2)
    -18.1 ( 2.617 )
    -52.6 ( 1.791 )
    No statistical analyses for this end point

    Other pre-specified: Change from Baseline in KCCQ Total Symptom Score at Months 12, 30, 42, 60 and 90: Cohort A

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    End point title
    		 Change from Baseline in KCCQ Total Symptom Score at Months 12, 30, 42, 60 and 90: Cohort A
    End point description
    KCCQ: 23-item, self-administered questionnaire assesses health status & health-related QoL in participants with heart failure. KCCQ has 8 domains: physical limitations, symptom stability, symptom frequency, symptom burden, total symptom (mean of symptom frequency and symptom burden), self-efficacy, quality of life & social limitations). Scores were generated for each domain and scaled from 0 (worst)-100 (best possible status). KCCQ Total Symptoms score=mean of the domains- symptom frequency & symptom burden and transformed to single score which ranged from 0 (worst)-100 (best possible status),higher scores=better health status. Data for change from baseline reported as LS mean. CMA set was analyzed. All participants reported under "Number of Participants Analyzed" contributed data to table; may not have evaluable data for every row. “n”=number of participants evaluable at specified time points.Therefore, this analysis was based on the pooled dose groups, as per the SAP.
    End point type
    Other pre-specified
    End point timeframe
    B3461028: Baseline (Day 1, pre-dose), Months 12, 30; B3461045: Months 42, 60 and 90 (time points were relative to Day 1 from B3461028; 42, 60 and 90 Months were 12, 30 and 60 Months of B3461045)
    End point values
    		 Cohort A: Tafamidis(Parent study) & Tafamidis(Extension Study) Cohort A: Placebo (Parent Study) & Tafamidis (Extension Study)
    Number of subjects analysed
    264
    177
    Units: Units on a scale
    least squares mean (standard error)
        Change at Month 12 (n= 221, 145)
    -2.90 ( 1.182 )
    -10.3 ( 1.494 )
        Change at Month 30 (n= 170, 84)
    -5.92 ( 1.279 )
    -18.7 ( 2.276 )
        Change at Month 42 (n= 143, 54)
    -9.29 ( 1.699 )
    -22.5 ( 2.237 )
        Change at Month 60 (n= 64, 22)
    -8.94 ( 1.858 )
    -19.0 ( 3.693 )
        Change at Month 90 (n= 9, 2)
    -16.4 ( 2.654 )
    -56.0 ( 1.958 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in KCCQ Clinical Summary Scores at Months 12, 30 and 54: Cohort B

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    End point title
    		 Change From Baseline in KCCQ Clinical Summary Scores at Months 12, 30 and 54: Cohort B [5]
    End point description
    KCCQ: 23-item, self-administered questionnaire assesses health status & health-related QoL in participants with heart failure. KCCQ has 8 domains: physical limitations, symptom stability, symptom frequency, symptom burden, total symptom (mean of symptom frequency and symptom burden), self-efficacy, quality of life and social limitations). Scores were generated for each domain and scaled from 0 (worst)-100 (best possible status). KCCQ-clinical summary score=mean of domains- physical limitation and total symptoms and transformed to single score which ranged from 0 (worst) -100 (best possible status), higher scores = better health status. Data for change from baseline reported as mean. Safety analysis set. All participants reported under "Number of Participants Analyzed" contributed data to table;may not have evaluable data for every row.“n”=number of participants evaluable at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: Baseline (Day 1, pre-dose), Months 12, 30 and 54
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is reporting statistics for the arms specified
    End point values
    		 Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    830
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Month 12 (n= 830)
    -0.242 ( 17.7032 )
        Change at Month 30 (n=237)
    -3.086 ( 20.4276 )
        Change at Month 54 (n=42)
    -3.988 ( 18.7931 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in KCCQ Overall Score at Months 12, 30 and 54: Cohort B

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    End point title
    		 Change From Baseline in KCCQ Overall Score at Months 12, 30 and 54: Cohort B [6]
    End point description
    KCCQ: 23-item, self-administered questionnaire assesses health status & health-related QoL in participants with heart failure. KCCQ has 8 domains:physical limitations, symptom stability,symptom frequency,symptom burden, total symptom(mean of symptom frequency and symptom burden),self-efficacy, quality of life & social limitations). Scores were generated for each domain and scaled from 0 (worst)-100 (best possible status). KCCQ-overall score=mean of domains-physical limitation, total symptoms, quality of life, social limitation & transformed to single score which ranged from 0 (worst)-100 (best possible status), higher scores=better health status. Data for change from baseline reported as mean. Safety analysis set. All participants reported under "Number of Participants Analyzed" contributed data to table; may not have evaluable data for every row. “n” =number of participants evaluable at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: Baseline (Day 1, pre-dose), Months 12, 30 and 54
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is reporting statistics for the arms specified
    End point values
    		 Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    830
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Month 12 (n= 830)
    0.443 ( 18.2575 )
        Change at Month 30 (n= 237)
    -1.378 ( 20.9437 )
        Change at Month 54 (n=42)
    -2.093 ( 19.5085 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in KCCQ Total Symptom Score at Months 12, 30 and 54: Cohort B

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    End point title
    		 Change From Baseline in KCCQ Total Symptom Score at Months 12, 30 and 54: Cohort B [7]
    End point description
    KCCQ: 23-item, self-administered questionnaire assesses health status & health-related QoL in participants with heart failure. KCCQ has 8 domains: physical limitations, symptom stability, symptom frequency, symptom burden, total symptom(mean of symptom frequency and symptom burden),self-efficacy, quality of life & social limitations). Scores were generated for each domain and scaled from 0 (worst)-100 (best possible status). KCCQ Total Symptoms score=mean of the domains- symptom frequency & symptom burden and transformed to single score which ranged from 0 (worst)-100 (best possible status),higher scores=better health status. Data for change from baseline reported as mean. Safety analysis set. All participants reported under "Number of Participants Analyzed" contributed data to table; may not have evaluable data for every row.“n”=number of participants evaluable at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: Baseline (Day 1, pre-dose), Months 12, 30 and 54
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is reporting statistics for the arms specified
    End point values
    		 Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    829
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Month 12 (n= 829)
    0.738 ( 19.1549 )
        Change at Month 30 (n= 237)
    -1.112 ( 20.7952 )
        Change at Month 54 (n=42)
    -1.885 ( 19.4433 )
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Shift From Baseline in New York Heart Association (NYHA) Classification at Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60

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    End point title
    		 Number of Participants With Shift From Baseline in New York Heart Association (NYHA) Classification at Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    End point description
    NYHA classification:Class(Cl)I:Participants with Cardiovascular disease (CVD) but without resulting limitation of physical activity(PA).Ordinary PA does not cause fatigue,palpitation,dyspnea or anginal pain;Cl II:Participants with CVD resulting in slight limitation of PA&comfortable at rest.Ordinary PA results in fatigue,palpitation,dyspnea or angina pain;Cl III:participants with CVD resulting in marked limitation of PA&comfortable at rest.Less than ordinary PA causes fatigue,palpitation,dyspnea or anginal pain;Cl IV:participants with CVD resulting in inability to carry on any PA without discomfort.Symptoms of cardiac insufficiency/anginal syndrome may present even at rest.If any PA is undertaken,discomfort is increased.Safety analysis set.All participants reported"No.of Participants Analyzed"contributed data to table,may not evaluable data for every row.n=participants evaluable at specified timepoints.Analysis(Cohort A)based on pooled dose groups,as per SAP.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: Baseline (Day 1, pre-dose), Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    End point values
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study) Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    170
    82
    1476
    Units: Participants
        Month 6 Cl I (Baseline) to Cl I (n=155, 66, 1249)
    13
    4
    132
        Month 12 Cl I (Baseline) to Cl I (n= 142,54,850)
    10
    4
    94
        Month 18 Cl I (Baseline) to Cl I (n= 123, 47, 611)
    5
    4
    64
        Month 24 Cl I (Baseline) to Cl I (n=105,40,434)
    4
    4
    42
        Month 30 Cl I (Baseline) to Cl I (n=64,23,291)
    1
    1
    27
        Month 36 Cl I (Baseline) to Cl I (n= 43,17,223)
    1
    2
    21
        Month 42 Cl I (Baseline) to Cl I (n=31,8,163)
    0
    0
    16
        Month 48 Cl I (Baseline) to Cl I (n=27,7,99)
    0
    0
    6
        Month 54 Cl I (Baseline) to Cl I (n=18,4,44)
    0
    0
    1
        Month 60 Cl I (Baseline) to Cl I (n= 9,2,0)
    0
    0
    0
        Month 6 Cl I (Baseline) to Cl II (n=155,66,1249)
    4
    2
    70
        Month 12 Cl I (Baseline) to Cl II (n=142,54,850)
    5
    0
    60
        Month 18 Cl I (Baseline) to Cl II (n=123,47,611)
    3
    0
    45
        Month 24 Cl I (Baseline) to Cl II (n=105,40,434)
    4
    1
    40
        Month 30 Cl I (Baseline) to Cl II (n=64,23,291)
    1
    0
    32
        Month 36 Cl I (Baseline) to Cl II (n=43,17,223)
    4
    0
    18
        Month 42 Cl I (Baseline) to Cl II (n=31,8,163)
    3
    1
    11
        Month 48 Cl I (Baseline) to Cl II (n=27,7,99)
    2
    0
    8
        Month 54 Cl I (Baseline) to Cl II (n=18,4,44)
    0
    0
    3
        Month 60 Cl I (Baseline) to Cl II (n= 9,2,0)
    0
    0
    0
        Month 6 Cl I (Baseline) to Cl III (n=155,66,1249)
    0
    0
    8
        Month 12 Cl I (Baseline) to Cl III (n=142,54,850)
    1
    0
    3
        Month 18 Cl I (Baseline) to Cl III (n=123,47,611)
    0
    0
    3
        Month 24 Cl I (Baseline) to Cl III (n=105,40,434)
    2
    1
    0
        Month 30 Cl I (Baseline) to Cl III (n=64,23,291)
    0
    0
    1
        Month 36 Cl I (Baseline) to Cl III (n=43,17,223)
    0
    0
    0
        Month 42 Cl I (Baseline) to Cl III (n=31,8,163)
    0
    0
    1
        Month 48 Cl I (Baseline) to Cl III (n=27,7,99)
    0
    0
    0
        Month 54 Cl I (Baseline) to Cl III (n=18,4,44)
    0
    0
    0
        Month 60 Cl I (Baseline) to Cl III (n= 9,2,0)
    0
    0
    0
        Month 6 Cl I (Baseline) to Cl IV (n=155,66,1249)
    0
    0
    0
        Month 12 Cl I (Baseline) to Cl IV (n=142,54,850)
    0
    0
    0
        Month 18 Cl I (Baseline) to Cl IV (n=123,47,611)
    0
    0
    0
        Month 24 Cl I (Baseline) to Cl IV (n=105,40,434)
    0
    0
    0
        Month 30 Cl I (Baseline) to Cl IV (n=64,23,291)
    0
    0
    0
        Month 36 Cl I (Baseline) to Cl IV (n=43,17,223)
    0
    0
    0
        Month 42 Cl I (Baseline) to Cl IV (n=31,8,163)
    0
    0
    0
        Month 48 Cl I (Baseline) to Cl IV (n=27,7,99)
    0
    0
    0
        Month 54 Cl I (Baseline) to Cl IV (n=18,4,44)
    0
    0
    0
        Month 60 Cl I (Baseline) to Cl IV (n= 9,2,0)
    0
    0
    0
        Month 6 Cl II (Baseline) to Cl I (n=155,66,1249)
    7
    0
    60
        Month 12 Cl II (Baseline) to Cl I (n=142,54,850)
    6
    0
    50
        Month 18 Cl II (Baseline) to Cl I (n=123,47,611)
    8
    0
    41
        Month 24 Cl II (Baseline) to Cl I (n=105,40,434)
    8
    0
    31
        Month 30 Cl II (Baseline) to Cl I (n=64,23,291)
    5
    1
    26
        Month 36 Cl II (Baseline) to Cl I (n=43,17,223)
    3
    0
    19
        Month 42 Cl II (Baseline) to Cl I (n=31,8,163)
    4
    1
    9
        Month 48 Cl II (Baseline) to Cl I (n=27,7,99)
    2
    1
    2
        Month 54 Cl II (Baseline) to Cl I (n=18,4,44)
    0
    0
    1
        Month 60 Cl II (Baseline) to Cl I (n= 9,2,0)
    0
    0
    0
        Month 6 Cl II (Baseline) to Cl II (n=155,66,1249)
    65
    20
    542
        Month 12 Cl II (Baseline) to Cl II (n=142,54,850)
    63
    16
    371
        Month 18 Cl II (Baseline) to Cl II (n=123,47,611)
    49
    15
    259
        Month 24 Cl II (Baseline) to Cl II (n=105,40,434)
    49
    12
    191
        Month 30 Cl II (Baseline) to Cl II (n=64,23,291)
    27
    7
    129
        Month 36 Cl II (Baseline) to Cl II (n= 43,17,223)
    19
    7
    101
        Month 42 Cl II (Baseline) to Cl II (n=31,8,163)
    14
    4
    77
        Month 48 Cl II (Baseline) to Cl II (n=27,7,99)
    12
    4
    54
        Month 54 Cl II (Baseline) to Cl II (n=18,4,44)
    7
    3
    22
        Month 60 Cl II (Baseline) to Cl II (n= 9,2,0)
    4
    0
    0
        Month 6 Cl II (Baseline) to Cl III (n=155,66,1249)
    11
    2
    100
        Month 12 Cl II (Baseline) to Cl III (n=142,54,850)
    10
    1
    67
        Month 18 Cl II (Baseline) to Cl III (n=123,47,611)
    9
    1
    61
        Month 24 Cl II (Baseline) to Cl III (n=105,40,434)
    3
    0
    42
        Month 30 Cl II (Baseline) to Cl III (n=64,23,291)
    2
    1
    24
        Month 36 Cl II (Baseline) to Cl III (n=43,17,223)
    2
    1
    25
        Month 42 Cl II (Baseline) to Cl III (n=31,8,163)
    2
    0
    16
        Month 48 Cl II (Baseline) to Cl III (n=27,7,99)
    2
    0
    7
        Month 54 Cl II (Baseline) to Cl III (n=18,4,44)
    2
    0
    6
        Month 60 Cl II (Baseline) to Cl III (n= 9,2,0)
    2
    0
    0
        Month 6 Cl II (Baseline) to Cl IV (n=155,66,1249)
    0
    0
    1
        Month 12 Cl II (Baseline) to Cl IV (n= 142,54,850)
    1
    0
    1
        Month 18 Cl II (Baseline) to Cl IV (n= 123,47,611)
    0
    0
    1
        Month 24 Cl II (Baseline) to Cl IV (n=105,40,434)
    0
    0
    0
        Month 30 Cl II (Baseline) to Cl IV (n=64,23,291)
    0
    0
    0
        Month 36 Cl II (Baseline) to Cl IV (n=43,17,223)
    0
    0
    0
        Month 42 Cl II (Baseline) to Cl IV (n=31,8,163)
    0
    0
    0
        Month 48 Cl II (Baseline) to Cl IV (n=27,7,99)
    0
    0
    0
        Month 54 Cl II (Baseline) to Cl IV (n=18,4,44)
    0
    0
    0
        Month 60 Cl II (Baseline) to Cl IV (n= 9,2,0)
    0
    0
    0
        Month 6 Cl III (Baseline) to Cl I (n=155,66,1249)
    1
    0
    4
        Month 12 Cl III (Baseline) to Cl I (n=142,54,850)
    3
    0
    1
        Month 18 Cl III (Baseline) to Cl I (n=123,47,611)
    2
    0
    5
        Month 24 Cl III (Baseline) to Cl I (n=105,40,434)
    4
    0
    3
        Month 30 Cl III (Baseline) to Cl I (n=64,23,291)
    4
    0
    2
        Month 36 Cl III (Baseline) to Cl I (n=43,17,223)
    1
    0
    3
        Month 42 Cl III (Baseline) to Cl I (n=31,8,163)
    1
    0
    1
        Month 48 Cl III (Baseline) to Cl I (n=27,7,99)
    2
    0
    0
        Month 54 Cl III (Baseline) to Cl I (n=18,4,44)
    3
    0
    0
        Month 60 Cl III (Baseline) to Cl I (n= 9,2,0)
    1
    0
    0
        Month 6 Cl III (Baseline) to Cl II (n=155,66,1249)
    17
    9
    88
        Month 12 Cl III (Baseline) to Cl II (n=142,54,850)
    12
    9
    67
        Month 18 Cl III (Baseline) to Cl II (n=123,47,611)
    19
    6
    57
        Month 24 Cl III (Baseline) to Cl II (n=105,40,434)
    11
    8
    34
        Month 30 Cl III (Baseline) to Cl II (n=64,23,291)
    14
    4
    22
        Month 36 Cl III (Baseline) to Cl II (n=43,17,223)
    5
    2
    21
        Month 42 Cl III (Baseline) to Cl II (n=31,8,163)
    3
    1
    20
        Month 48 Cl III (Baseline) to Cl II (n=27,7,99)
    3
    1
    8
        Month 54 Cl III (Baseline) to Cl II (n=18,4,44)
    3
    1
    4
        Month 60 Cl III (Baseline) to Cl II (n= 9,2,0)
    1
    2
    0
        Month6 Cl III(Baseline) to Cl III (n=155,66,1249)
    34
    24
    226
        Month12 Cl III (Baseline) to Cl III (n=142,54,850)
    31
    23
    127
        Month18 Cl III(Baseline) to Cl III (n=123,47,611)
    24
    19
    70
        Month24 Cl III(Baseline) to Cl III (n=105,40,434)
    17
    14
    46
        Month30 Cl III(Baseline) to Cl III (n=64,23,291)
    10
    9
    24
        Month36 Cl III(Baseline) to Cl III (n= 43,17,223)
    7
    4
    14
        Month42Cl III(Baseline) to Cl III (n=31,8,163)
    4
    1
    12
        Month48 Cl III(Baseline) to Cl III (n=27,7,99)
    4
    1
    13
        Month54 Cl III(Baseline) to Cl III (n=18,4,44)
    3
    0
    7
        Month60 Cl III(Baseline) to Cl III (n= 9,2,0)
    1
    0
    0
        Month6 Cl III(Baseline) to Cl IV (n=155,66,1249)
    0
    0
    2
        Month12 Cl III (Baseline) to Cl IV (n=142,54,850)
    0
    0
    0
        Month 18 Cl III (Baseline) to Cl IV (n=123,47,611)
    0
    0
    0
        Month 24 Cl III (Baseline) to Cl IV (n=105,40,434)
    0
    0
    0
        Month30 Cl III(Baseline) to Cl IV (n=64, 23, 291)
    0
    0
    0
        Month36 Cl III(Baseline) to Cl IV (n= 43,17,223)
    0
    0
    0
        Month42 Cl III(Baseline) to Cl IV (n=31,8,163)
    0
    0
    0
        Month48 Cl III(Baseline) to Cl IV (n=27,7,99)
    0
    0
    0
        Month54 Cl III(Baseline) to Cl IV (n=18,4,44)
    0
    0
    0
        Month60 Cl III(Baseline) to Cl IV (n= 9,2,0)
    0
    0
    0
        Month 6 Cl IV (Baseline) to Cl I (n=155,66,1249)
    0
    0
    1
        Month 12 Cl IV (Baseline) to Cl I (n= 142,54,850)
    0
    0
    0
        Month 18 Cl IV (Baseline) to Cl I (n= 123,47,611)
    2
    0
    0
        Month 24 Cl IV (Baseline) to Cl I (n=105,40,434)
    0
    0
    0
        Month 30 Cl IV (Baseline) to Cl I (n=64,23,291)
    0
    0
    0
        Month 36 Cl IV (Baseline) to Cl I (n= 43,17,223)
    0
    0
    0
        Month 42 Cl IV (Baseline) to Cl I (n=31,8,163)
    0
    0
    0
        Month 48 Cl IV (Baseline) to Cl I (n=27,7,99)
    0
    0
    0
        Month 54 Cl IV (Baseline) to Cl I (n=18,4,44)
    0
    0
    0
        Month 60 Cl IV (Baseline) to Cl I (n= 9,2,0)
    0
    0
    0
        Month 6 Cl IV (Baseline) to Cl II (n=155,66,1249)
    1
    1
    2
        Month 12 Cl IV (Baseline) to Cl II (n=142,54,850)
    0
    0
    1
        Month 18 Cl IV (Baseline) to Cl II (n=123,47,611)
    0
    0
    2
        Month 24 Cl IV (Baseline) to Cl II (n=105,40,434)
    1
    0
    1
        Month 30 Cl IV (Baseline) to Cl II (n=64,23,291)
    0
    0
    2
        Month 36 Cl IV (Baseline) to Cl II (n= 43,17,223)
    1
    0
    1
        Month 42 Cl IV (Baseline) to Cl II (n=31,8,163)
    0
    0
    0
        Month 48 Cl IV (Baseline) to Cl II (n=27,7,99)
    0
    0
    0
        Month 54 Cl IV (Baseline) to Cl II (n=18,4,44)
    0
    0
    0
        Month 60 Cl IV (Baseline) to Cl II (n= 9,2,0)
    0
    0
    0
        Month 6 Cl IV (Baseline) to Cl III (n=155,66,1249)
    1
    3
    10
        Month 12 Cl IV (Baseline) to Cl III (n=142,54,850)
    0
    1
    7
        Month 18 Cl IV (Baseline) to Cl III (n=123,47,611)
    2
    2
    3
        Month 24 Cl IV (Baseline) to Cl III (n=105,40,434)
    2
    0
    4
        Month 30 Cl IV (Baseline) to Cl III (n=64,23,291)
    0
    0
    2
        Month 36 Cl IV (Baseline) to Cl III (n= 43,17,223)
    0
    1
    0
        Month 42 Cl IV (Baseline) to Cl III (n=31,8,163)
    0
    0
    0
        Month 48 Cl IV (Baseline) to Cl III (n=27,7,99)
    0
    0
    1
        Month 54 Cl IV (Baseline) to Cl III (n=18,4,44)
    0
    0
    0
        Month 60 Cl IV (Baseline) to Cl III (n= 9,2,0)
    0
    0
    0
        Month 6 Cl IV (Baseline) to Cl IV (n=155,66,1249)
    1
    1
    3
        Month 12 Cl IV (Baseline) to Cl IV (n=142,54,850)
    0
    0
    1
        Month 18 Cl IV (Baseline) to Cl IV (n=123,47,611)
    0
    0
    0
        Month 24 Cl IV (Baseline) to Cl IV (n=105,40,434)
    0
    0
    0
        Month 30 Cl IV (Baseline) to Cl. IV (n=64,23,291)
    0
    0
    0
        Month 36 Cl IV (Baseline) to Cl IV (n=43,17,223)
    0
    0
    0
        Month 42 Cl IV (Baseline) to Cl IV (n=31,8,163)
    0
    0
    0
        Month 48 Cl IV (Baseline) to Cl IV (n=27,7,99)
    0
    0
    0
        Month 54 Cl IV (Baseline) to Cl IV (n=18,4,44)
    0
    0
    0
        Month 60 Cl IV (Baseline) to Cl IV (n= 9,2,0)
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Body Mass Index (BMI) at Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60

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    End point title
    		 Change From Baseline in Body Mass Index (BMI) at Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    End point description
    BMI was calculated as: body weight in kilogram (kg) divided by (/) square of body height measurement in meters square (m^2). Safety analysis population included all participants (Cohorts A and B) who were enrolled in this study and taken at least 1 dose of study medication. All participants reported under "Number of Participants Analyzed" contributed data to the table; however, may not have evaluable data for every row. “n” signifies number of participants evaluable at specified time points.99999 indicates Arithmetic Mean and Standard Deviation was not estimable as there were no participants. Therefore, this analysis was based on the pooled dose groups, as per the SAP.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: Baseline (Day 1, pre-dose), Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    End point values
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study) Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    170
    82
    1476
    Units: kg/m^2
    arithmetic mean (standard deviation)
        Change at Month 6 (n= 155, 67, 1216)
    -0.07 ( 0.873 )
    -0.27 ( 0.900 )
    -0.24 ( 1.234 )
        Change at Month 12 (n= 141, 54, 800)
    -0.21 ( 1.212 )
    -0.40 ( 1.440 )
    -0.20 ( 1.552 )
        Change at Month 18 (n=122, 47, 555)
    -0.38 ( 1.442 )
    -0.85 ( 1.502 )
    -0.30 ( 1.956 )
        Change at Month 24 (n= 104, 40, 418)
    -0.36 ( 1.407 )
    -0.78 ( 1.668 )
    -0.43 ( 1.747 )
        Change at Month 30 (n= 62, 23, 287)
    -0.71 ( 1.423 )
    -1.28 ( 1.814 )
    -0.41 ( 1.802 )
        Change at Month 36 (n= 41, 16, 220)
    -1.18 ( 2.200 )
    -0.49 ( 1.852 )
    -0.69 ( 1.730 )
        Change at Month 42 (n=30, 8, 162)
    -0.91 ( 1.402 )
    -0.11 ( 1.523 )
    -0.74 ( 1.827 )
        Change at Month 48 (n= 27, 7, 100)
    -1.14 ( 1.480 )
    -0.01 ( 1.927 )
    -0.83 ( 1.732 )
        Change at Month 54 (n=18, 4, 44)
    -1.03 ( 1.716 )
    -1.54 ( 0.528 )
    -1.24 ( 1.942 )
        Change at Month 60 (n= 9, 2, 0)
    -0.93 ( 2.102 )
    -1.62 ( 0.834 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Modified Body Mass Index (mBMI) at Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60

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    End point title
    		 Change From Baseline in Modified Body Mass Index (mBMI) at Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    End point description
    Modified (m)BMI of participants was calculated to determine if there was any gastrointestinal involvement in participants. The mBMI was calculated by multiplying BMI by serum albumin concentration gram/liter (g/L). Safety analysis population included all participants (Cohorts A and B) who were enrolled in this study and taken at least 1 dose of study medication. All participants reported under "Number of Participants Analyzed" contributed data to the table; however, may not have evaluable data for every row. “n” signifies number of participants evaluable at specified time points. Here, 88888 indicates Standard Deviation was not estimable as there was only one participant. 99999 indicates Arithmetic Mean and Standard Deviation was not estimable as there were no participants. This analysis (cohort A) was based on the pooled dose groups, as per the SAP.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: Baseline (Day 1, pre-dose), Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    End point values
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study) Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    170
    82
    1476
    Units: (kg/m^2) *(g/L)
    arithmetic mean (standard deviation)
        Change at Month 6 (n= 154, 64, 1037)
    -2.96 ( 36.046 )
    -10.91 ( 36.338 )
    -8.51 ( 51.329 )
        Change at Month 12 (n= 140, 51, 674)
    -7.42 ( 49.840 )
    -16.09 ( 57.882 )
    -6.17 ( 66.094 )
        Change at Month 18 (n= 121, 44, 455)
    -15.46 ( 60.361 )
    -35.46 ( 63.390 )
    -10.08 ( 85.605 )
        Change at Month 24 (n= 104, 38, 345)
    -15.07 ( 58.706 )
    -32.33 ( 71.104 )
    -15.81 ( 74.009 )
        Change at Month 30 (n= 62, 22, 234)
    -29.31 ( 61.003 )
    -52.81 ( 78.705 )
    -15.70 ( 79.724 )
        Change at Month 36 (n= 41, 15, 172)
    -49.46 ( 98.257 )
    -17.81 ( 80.327 )
    -24.66 ( 74.366 )
        Change at Month 42 (n= 30, 7, 135)
    -36.32 ( 58.130 )
    1.59 ( 69.701 )
    -28.06 ( 78.987 )
        Change at Month 48 (n= 27, 6, 87)
    -46.43 ( 62.394 )
    14.05 ( 83.969 )
    -32.91 ( 71.745 )
        Change at Month 54 (n= 18, 3, 36)
    -41.98 ( 74.883 )
    -52.80 ( 14.562 )
    -51.15 ( 79.618 )
        Change at Month 60 (n= 9, 1, 0)
    -38.90 ( 92.253 )
    -41.20 ( 88888 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Troponin I Concentration at Month 6, 12 , 18, 24, 30, 36, 42, 48, 54 and 60

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    End point title
    		 Change From Baseline in Troponin I Concentration at Month 6, 12 , 18, 24, 30, 36, 42, 48, 54 and 60
    End point description
    NT-proBNP was a cardiac marker which had the prognostic value for participants with heart failure or left ventricular dysfunction. It was measure in nanogram per milliliter (ng/mL). Higher level of the marker was indicative of heart damage. Safety analysis population included all participants (Cohorts A and B) who were enrolled in this study and taken at least 1 dose of study medication. All participants reported under "Number of Participants Analyzed" contributed data to the table; however, may not have evaluable data for every row. “n” signifies number of participants evaluable at specified time points. Here, 88888 indicates Standard Deviation was not estimable as there was only one participant. 99999 indicates Arithmetic Mean and Standard Deviation was not estimable as there were no participants. This analysis (cohort A) was based on the pooled dose groups, as per the SAP.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: Baseline (Day 1, pre-dose), Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    End point values
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study) Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    170
    82
    1476
    Units: ng/mL
    arithmetic mean (standard deviation)
        Change at Month 6 (n= 0, 0, 108)
    99999 ( 99999 )
    99999 ( 99999 )
    0.012 ( 0.1706 )
        Change at Month 12 (n= 165, 81, 99)
    0.035 ( 0.3977 )
    0.037 ( 0.0853 )
    0.009 ( 0.0893 )
        Change at Month 18 (n= 1, 0, 70)
    0.040 ( 88888 )
    99999 ( 99999 )
    -0.007 ( 0.0786 )
        Change at Month 24 (n= 2, 3, 64)
    0.000 ( 0.0566 )
    0.033 ( 0.0306 )
    -0.031 ( 0.2031 )
        Change at Month 30 (n= 168, 80, 64)
    0.022 ( 0.1599 )
    0.100 ( 0.1728 )
    -0.033 ( 0.2055 )
        Change at Month 36 (n= 27, 11, 64)
    0.009 ( 0.0579 )
    0.018 ( 0.1057 )
    -0.034 ( 0.1913 )
        Change at Month 42 (n= 26, 6, 24)
    -0.002 ( 0.0795 )
    -0.047 ( 0.0755 )
    -0.021 ( 0.2484 )
        Change at Month 48 (n= 26, 6, 2)
    0.016 ( 0.0795 )
    -0.067 ( 0.2040 )
    -0.100 ( 0.0000 )
        Change at Month 54 (n= 14, 3, 0)
    -0.033 ( 0.0792 )
    -0.363 ( 0.6080 )
    99999 ( 99999 )
        Change at Month 60 (n=8, 2, 0)
    -0.040 ( 0.0414 )
    0.035 ( 0.0354 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Month 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60

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    End point title
    		 Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Month 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    End point description
    NT-proBNP was a cardiac marker which had the prognostic value for participants with heart failure or left ventricular dysfunction. It was measure in picomole per liter (pmole/L). Higher level of the marker was indicative of heart damage. Safety analysis population included all participants (Cohorts A and B) who were enrolled in this study and taken at least 1 dose of study medication. All participants reported under "Number of Participants Analyzed" contributed data to the table; however, may not have evaluable data for every row. “n” signifies number of participants evaluable at specified time points. Here, 88888 indicates Standard Deviation was not estimable as there was only one participant. 99999 indicates Arithmetic Mean and Standard Deviation was not estimable as there were no participants. This analysis (cohort A) was based on the pooled dose groups, as per the SAP.
    End point type
    Other pre-specified
    End point timeframe
    B3461045: Baseline (Day 1, pre-dose), Months 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60
    End point values
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study) Cohort B: Tafamidis (Only in extension study)
    Number of subjects analysed
    170
    82
    1476
    Units: pmole/L
    arithmetic mean (standard deviation)
        Change at Month 6 (n= 0, 0, 108)
    99999 ( 99999 )
    99999 ( 99999 )
    24.820 ( 171.2075 )
        Change at Month 12 (n= 167, 80, 101)
    31.117 ( 220.9279 )
    127.973 ( 226.7727 )
    32.686 ( 180.4921 )
        Change at Month 18 (n= 1, 0, 79)
    226.442 ( 88888 )
    99999 ( 99999 )
    71.582 ( 329.5411 )
        Change at Month 24 (n= 2, 3, 69)
    131.334 ( 119.5258 )
    256.442 ( 101.8073 )
    92.899 ( 320.6054 )
        Change at Month 30 (n= 170, 81, 70)
    159.596 ( 404.8483 )
    417.682 ( 597.9224 )
    149.049 ( 320.8814 )
        Change at Month 36 (n= 29, 11, 63)
    322.963 ( 215.1605 )
    420.196 ( 251.8446 )
    88.895 ( 227.7375 )
        Change at Month 42 (n= 26, 6, 24)
    419.034 ( 315.6436 )
    324.211 ( 173.6652 )
    191.318 ( 482.3582 )
        Change at Month 48 (n= 26, 6, 2)
    492.154 ( 387.4700 )
    400.571 ( 228.4343 )
    264.566 ( 78.7059 )
        Change at Month 54 (n= 17, 3, 0)
    405.887 ( 457.6349 )
    340.082 ( 190.6412 )
    99999 ( 99999 )
        Change at Month 60 (n= 9, 2, 0)
    392.363 ( 271.2883 )
    314.184 ( 274.6756 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    B3461045: From first dose of treatment up to 28 days post last dose of study treatment (approximately up to 61 months)
    Adverse event reporting additional description
    Same event may appear as non-SAE & SAE,what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another,or participant may have experienced both SAE & non-SAE. Safety analysis population consisted of all participants who were enrolled in this study & taken at least 1 dose of study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Cohort A: Tafamidis (Parent and Extension Study)
    Reporting group description
    		 Participants who received tafamidis 20 mg or 80 mg orally once daily in the parent study for 30 months (complete participation), after enrollment in the current extension study, continued to receive the same dose and later switched to tafamidis 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), orally once daily along with standard of care for up to 60 months.

    Reporting group title
    Cohort B: Tafamidis (Only in extension study)
    Reporting group description
    		 Participants who did not participate in the parent study and received tafamidis at a dose of 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), once daily along with standard of care for up to 60 months.

    Reporting group title
    Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study)
    Reporting group description
    		 Participants who received placebo orally once daily in the parent study for 30 months (complete participation), after enrollment in the current extension study, received tafamidis 20 mg or 80 mg and later switched to tafamidis 61 mg (or 80 mg in regions where 61 mg tafamidis was unavailable), orally once daily along with standard of care for up to 60 months.

    Serious adverse events
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort B: Tafamidis (Only in extension study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    132 / 170 (77.65%)
    736 / 1476 (49.86%)
    64 / 82 (78.05%)
         number of deaths (all causes)
    45
    203
    33
         number of deaths resulting from adverse events
    40
    198
    32
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 170 (0.59%)
    4 / 1476 (0.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal neoplasm
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Anal squamous cell carcinoma
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Basal cell carcinoma
         subjects affected / exposed
    2 / 170 (1.18%)
    9 / 1476 (0.61%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma recurrent
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Bowen's disease
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Cancer pain
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Central nervous system melanoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 myelomonocytic leukaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hormone-dependent prostate cancer
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Malignant melanoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome with excess blasts
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Neoplasm
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma metastatic
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Non-small cell lung cancer stage IIIB
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 squamous cell carcinoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Oncocytoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Primary pulmonary melanoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
         subjects affected / exposed
    3 / 170 (1.76%)
    5 / 1476 (0.34%)
    0 / 82 (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
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 170 (0.59%)
    6 / 1476 (0.41%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    0 / 82 (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
    Vascular disorders
    Distributive shock
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Circulatory collapse
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Bleeding varicose vein
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Axillary vein thrombosis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 fistula
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Aortic stenosis
         subjects affected / exposed
    0 / 170 (0.00%)
    10 / 1476 (0.68%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 11
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Embolism
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hypertensive emergency
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    2 / 170 (1.18%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Extremity necrosis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Embolism venous
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hypertensive urgency
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hypotension
         subjects affected / exposed
    2 / 170 (1.18%)
    16 / 1476 (1.08%)
    4 / 82 (4.88%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 16
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Shock
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Iliac artery stenosis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 limb pain
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 venous thrombosis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Peripheral embolism
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (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
    Peripheral ischaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Peripheral vein stenosis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Shock haemorrhagic
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Venous thrombosis limb
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Surgical and medical procedures
    Therapy change
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         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 ablation
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Implantable defibrillator insertion
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Muscle electrostimulation therapy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Wound treatment
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Asthenia
         subjects affected / exposed
    2 / 170 (1.18%)
    5 / 1476 (0.34%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    4 / 170 (2.35%)
    5 / 1476 (0.34%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 170 (0.00%)
    7 / 1476 (0.47%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    7 / 7
    1 / 1
    Discomfort
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Fatigue
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 170 (0.59%)
    11 / 1476 (0.75%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 13
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    Generalised oedema
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hypothermia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Implant site haematoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    4 / 170 (2.35%)
    22 / 1476 (1.49%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 22
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 22
    0 / 3
    Multi-organ disorder
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Oedema peripheral
         subjects affected / exposed
    0 / 170 (0.00%)
    6 / 1476 (0.41%)
    0 / 82 (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
    Pain
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (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
    Sudden death
         subjects affected / exposed
    0 / 170 (0.00%)
    6 / 1476 (0.41%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    6 / 6
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Immune system disorders
    Acquired ATTR amyloidosis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Amyloidosis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Graft versus host disease
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Primary amyloidosis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Prostatitis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Prostatomegaly
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Scrotal swelling
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 prostatic hyperplasia
         subjects affected / exposed
    1 / 170 (0.59%)
    5 / 1476 (0.34%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (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
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Acute respiratory failure
         subjects affected / exposed
    3 / 170 (1.76%)
    7 / 1476 (0.47%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 170 (1.18%)
    5 / 1476 (0.34%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hypoxia
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Interstitial lung disease
         subjects affected / exposed
    1 / 170 (0.59%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Dyspnoea
         subjects affected / exposed
    3 / 170 (1.76%)
    13 / 1476 (0.88%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 13
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 170 (1.76%)
    10 / 1476 (0.68%)
    4 / 82 (4.88%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 11
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cough
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Organising pneumonia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 amyloidosis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    0 / 82 (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
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 hypertension
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (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
    Pulmonary infarction
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 toxicity
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Respiratory disorder
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 170 (0.59%)
    12 / 1476 (0.81%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 13
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 170 (0.59%)
    7 / 1476 (0.47%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Anxiety
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Completed suicide
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Confusional state
         subjects affected / exposed
    0 / 170 (0.00%)
    6 / 1476 (0.41%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Depressed mood
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hallucination
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Major depression
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Mental status changes
         subjects affected / exposed
    2 / 170 (1.18%)
    4 / 1476 (0.27%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mixed anxiety and depressive disorder
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Delirium
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device loosening
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 capturing issue
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 failure
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 inappropriate shock delivery
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    2 / 170 (1.18%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Device occlusion
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac cirrhosis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Cholecystitis acute
         subjects affected / exposed
    0 / 170 (0.00%)
    5 / 1476 (0.34%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Congestive hepatopathy
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    2 / 170 (1.18%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hepatitis acute
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hepatomegaly
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Ischaemic hepatitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Jaundice
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Investigations
    Blood potassium abnormal
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Apnoea test
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 urea increased
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial aspiration procedure
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Ejection fraction
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Ejection fraction decreased
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Haemoglobin decreased
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Peritoneal fluid analysis
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    0 / 82 (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
    Troponin increased
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (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
    International normalised ratio increased
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Chest injury
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Complications of transplanted kidney
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Acetabulum fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac procedure complication
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Contusion
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Craniocerebral injury
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Craniofacial fracture
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Fall
         subjects affected / exposed
    10 / 170 (5.88%)
    25 / 1476 (1.69%)
    5 / 82 (6.10%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 26
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Fat embolism
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Femoral neck fracture
         subjects affected / exposed
    1 / 170 (0.59%)
    2 / 1476 (0.14%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Foot fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Head injury
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    9 / 1476 (0.61%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (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
    Ilium fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    2 / 170 (1.18%)
    4 / 1476 (0.27%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Muscle strain
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Nasal injury
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Overdose
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Pelvic fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic osteolysis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 constipation
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 haematoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 haematuria
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 haemorrhage
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 pneumothorax
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Pulmonary contusion
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 170 (0.59%)
    4 / 1476 (0.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (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
    Seroma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Skin abrasion
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Spinal compression fracture
         subjects affected / exposed
    3 / 170 (1.76%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Splenic injury
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Splenic rupture
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    1 / 170 (0.59%)
    10 / 1476 (0.68%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Radius fracture
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Toxicity to various agents
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Urinary tract stoma complication
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Vasoplegia syndrome
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Wound haemorrhage
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Wrist fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         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
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Congenital, familial and genetic disorders
    Familial amyloidosis
         subjects affected / exposed
    4 / 170 (2.35%)
    10 / 1476 (0.68%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
    Hereditary neuropathic amyloidosis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Acute left ventricular failure
         subjects affected / exposed
    2 / 170 (1.18%)
    7 / 1476 (0.47%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Bifascicular block
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 170 (0.59%)
    16 / 1476 (1.08%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 16
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    4 / 170 (2.35%)
    8 / 1476 (0.54%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    4 / 170 (2.35%)
    18 / 1476 (1.22%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 18
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    11 / 170 (6.47%)
    62 / 1476 (4.20%)
    8 / 82 (9.76%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 79
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Arrhythmia
         subjects affected / exposed
    3 / 170 (1.76%)
    2 / 1476 (0.14%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Angina pectoris
         subjects affected / exposed
    2 / 170 (1.18%)
    11 / 1476 (0.75%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 170 (1.18%)
    11 / 1476 (0.75%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 11
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 170 (1.18%)
    7 / 1476 (0.47%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bundle branch block bilateral
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Cardiomyopathy
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Cardiogenic shock
         subjects affected / exposed
    3 / 170 (1.76%)
    20 / 1476 (1.36%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 22
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 9
    0 / 0
    Cardio-respiratory distress
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac flutter
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    17 / 170 (10.00%)
    52 / 1476 (3.52%)
    14 / 82 (17.07%)
         occurrences causally related to treatment / all
    0 / 24
    0 / 60
    0 / 19
         deaths causally related to treatment / all
    0 / 4
    0 / 6
    0 / 6
    Cardiac failure chronic
         subjects affected / exposed
    1 / 170 (0.59%)
    10 / 1476 (0.68%)
    4 / 82 (4.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 12
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    13 / 170 (7.65%)
    48 / 1476 (3.25%)
    10 / 82 (12.20%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 60
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
    Cardiac failure
         subjects affected / exposed
    30 / 170 (17.65%)
    169 / 1476 (11.45%)
    17 / 82 (20.73%)
         occurrences causally related to treatment / all
    0 / 55
    1 / 255
    0 / 30
         deaths causally related to treatment / all
    0 / 7
    0 / 33
    0 / 6
    Cardiac arrest
         subjects affected / exposed
    6 / 170 (3.53%)
    14 / 1476 (0.95%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 14
    0 / 3
         deaths causally related to treatment / all
    1 / 2
    0 / 13
    0 / 2
    Cardiac amyloidosis
         subjects affected / exposed
    2 / 170 (1.18%)
    16 / 1476 (1.08%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 17
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 12
    0 / 2
    Bundle branch block right
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Bundle branch block left
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    0 / 82 (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
    Myocardial infarction
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Low cardiac output syndrome
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 170 (0.59%)
    6 / 1476 (0.41%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Coronary artery stenosis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Coronary artery disease
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Conduction disorder
         subjects affected / exposed
    0 / 170 (0.00%)
    5 / 1476 (0.34%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic left ventricular failure
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Cardiorenal syndrome
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery embolism
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Sinoatrial block
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 arrest
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Sinus node dysfunction
         subjects affected / exposed
    1 / 170 (0.59%)
    10 / 1476 (0.68%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 170 (0.00%)
    7 / 1476 (0.47%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nodal arrhythmia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Nodal rhythm
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Palpitations
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Paroxysmal atrioventricular block
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    3 / 170 (1.76%)
    2 / 1476 (0.14%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Restrictive cardiomyopathy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Right ventricular dysfunction
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Right ventricular failure
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Torsade de pointes
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Ventricular dysfunction
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    0 / 82 (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
    Ventricular tachycardia
         subjects affected / exposed
    3 / 170 (1.76%)
    17 / 1476 (1.15%)
    6 / 82 (7.32%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 18
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Brain compression
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Brain injury
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Cerebral artery embolism
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Ataxia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 170 (1.18%)
    17 / 1476 (1.15%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 17
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Cognitive disorder
         subjects affected / exposed
    0 / 170 (0.00%)
    6 / 1476 (0.41%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Coma
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Dementia
         subjects affected / exposed
    3 / 170 (1.76%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Dysarthria
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Encephalopathy
         subjects affected / exposed
    3 / 170 (1.76%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Haemorrhagic transformation stroke
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    0 / 170 (0.00%)
    5 / 1476 (0.34%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    2 / 170 (1.18%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Neuralgia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Neuropathy peripheral
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Polyneuropathy
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Lethargy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Radiculopathy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hemianopia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Hemianopia homonymous
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hepatic encephalopathy
         subjects affected / exposed
    2 / 170 (1.18%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 170 (0.59%)
    11 / 1476 (0.75%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 12
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    0 / 82 (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
    Seizure
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Somnolence
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    6 / 170 (3.53%)
    42 / 1476 (2.85%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 43
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 170 (0.00%)
    9 / 1476 (0.61%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Vascular dementia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Vascular encephalopathy
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uraemic encephalopathy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 170 (1.18%)
    17 / 1476 (1.15%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 24
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Spontaneous haematoma
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Normochromic normocytic anaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Leukocytosis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 thrombocytopenia
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deficiency anaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Coagulopathy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 loss anaemia
         subjects affected / exposed
    1 / 170 (0.59%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Aplastic anaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Vertigo
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Blindness unilateral
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Charles Bonnet syndrome
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Optic ischaemic neuropathy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Orbital haematoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Vision blurred
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 pain upper
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Abdominal adhesions
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Abdominal discomfort
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Abdominal distension
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Abdominal pain
         subjects affected / exposed
    0 / 170 (0.00%)
    6 / 1476 (0.41%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Acute abdomen
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Appendiceal mucocoele
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Ascites
         subjects affected / exposed
    2 / 170 (1.18%)
    8 / 1476 (0.54%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Colitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Colitis microscopic
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 haemorrhage
         subjects affected / exposed
    4 / 170 (2.35%)
    13 / 1476 (0.88%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 15
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Dysphagia
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Faecaloma
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Constipation
         subjects affected / exposed
    2 / 170 (1.18%)
    2 / 1476 (0.14%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 vascular malformation haemorrhagic
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Haemorrhoids
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 / 170 (0.00%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Incarcerated umbilical hernia
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Intestinal obstruction
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Pneumoperitoneum
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Portal hypertensive gastropathy
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    3 / 170 (1.76%)
    7 / 1476 (0.47%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 170 (0.59%)
    4 / 1476 (0.27%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Melaena
         subjects affected / exposed
    1 / 170 (0.59%)
    4 / 1476 (0.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mesenteric vascular insufficiency
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Nausea
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal motility disorder
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Large intestine polyp
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 170 (0.59%)
    6 / 1476 (0.41%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 170 (0.59%)
    4 / 1476 (0.27%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulite
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Actinic keratosis
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Skin ulcer
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Rash papular
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Rash maculo-papular
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Pruritus
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Hyperhidrosis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Stasis dermatitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Eczema
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    16 / 170 (9.41%)
    34 / 1476 (2.30%)
    13 / 82 (15.85%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 42
    0 / 15
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    Chronic kidney disease
         subjects affected / exposed
    0 / 170 (0.00%)
    7 / 1476 (0.47%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    End stage renal disease
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Haematuria
         subjects affected / exposed
    3 / 170 (1.76%)
    8 / 1476 (0.54%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 12
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage urinary tract
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 / 170 (0.59%)
    5 / 1476 (0.34%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Polyuria
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 disorder
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 impairment
         subjects affected / exposed
    0 / 170 (0.00%)
    7 / 1476 (0.47%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Renal pseudoaneurysm
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Ureterolithiasis
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (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
    Urinary retention
         subjects affected / exposed
    3 / 170 (1.76%)
    7 / 1476 (0.47%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 170 (0.00%)
    9 / 1476 (0.61%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Back pain
         subjects affected / exposed
    2 / 170 (1.18%)
    4 / 1476 (0.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immunoglobulin G4 related disease
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Dupuytren's contracture
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Gouty arthritis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Greater trochanteric pain syndrome
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Haemarthrosis
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (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
    Haematoma muscle
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Chondrocalcinosis
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 170 (0.59%)
    4 / 1476 (0.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Osteoarthritis
         subjects affected / exposed
    2 / 170 (1.18%)
    9 / 1476 (0.61%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Pain in extremity
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Pathological fracture
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 stenosis
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    0 / 82 (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
    Tendonitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Osteonecrosis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Abscess limb
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Bacteraemia
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Beta haemolytic streptococcal infection
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Bronchitis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    COVID-19
         subjects affected / exposed
    2 / 170 (1.18%)
    16 / 1476 (1.08%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 16
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 170 (0.59%)
    9 / 1476 (0.61%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiac infection
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Cellulitis
         subjects affected / exposed
    8 / 170 (4.71%)
    18 / 1476 (1.22%)
    5 / 82 (6.10%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 20
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Bronchitis viral
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Diverticulitis intestinal perforated
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Endocarditis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Endophthalmitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 170 (0.59%)
    4 / 1476 (0.27%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Extradural abscess
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Diverticulitis
         subjects affected / exposed
    0 / 170 (0.00%)
    5 / 1476 (0.34%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Haematoma infection
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hepatitis A
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Herpes zoster
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    Herpes zoster meningoencephalitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 infection
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster meningomyelitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Implant site infection
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Infectious pleural effusion
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Influenza
         subjects affected / exposed
    1 / 170 (0.59%)
    2 / 1476 (0.14%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         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 respiratory tract infection
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Meningitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Meningitis bacterial
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Necrotising fasciitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Legionella infection
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Pericarditis infective
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Peritonitis
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Peritonsillar abscess
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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
    12 / 170 (7.06%)
    39 / 1476 (2.64%)
    9 / 82 (10.98%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 49
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
    Pneumonia aspiration
         subjects affected / exposed
    1 / 170 (0.59%)
    5 / 1476 (0.34%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 170 (0.59%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Pneumonia pneumococcal
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 streptococcal
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 viral
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 sepsis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory moniliasis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 tract infection
         subjects affected / exposed
    0 / 170 (0.00%)
    7 / 1476 (0.47%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Scrotal cellulitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    1 / 170 (0.59%)
    10 / 1476 (0.68%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Spontaneous bacterial peritonitis
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (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
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 170 (0.00%)
    3 / 1476 (0.20%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 sepsis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    8 / 170 (4.71%)
    17 / 1476 (1.15%)
    4 / 82 (4.88%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 17
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    Streptococcal sepsis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Superinfection fungal
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Tracheobronchitis
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Urinary tract infection
         subjects affected / exposed
    2 / 170 (1.18%)
    17 / 1476 (1.15%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 17
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 170 (0.59%)
    5 / 1476 (0.34%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Viral infection
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (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 respiratory tract infection
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Cachexia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Decreased appetite
         subjects affected / exposed
    1 / 170 (0.59%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Dehydration
         subjects affected / exposed
    0 / 170 (0.00%)
    7 / 1476 (0.47%)
    5 / 82 (6.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Electrolyte imbalance
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 1476 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 170 (0.00%)
    4 / 1476 (0.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Gout
         subjects affected / exposed
    1 / 170 (0.59%)
    9 / 1476 (0.61%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hyponatraemia
         subjects affected / exposed
    3 / 170 (1.76%)
    4 / 1476 (0.27%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 170 (1.18%)
    8 / 1476 (0.54%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hypervolaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    8 / 1476 (0.54%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    0 / 82 (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
    Hypokalaemia
         subjects affected / exposed
    2 / 170 (1.18%)
    9 / 1476 (0.61%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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
    Hypovolaemia
         subjects affected / exposed
    0 / 170 (0.00%)
    2 / 1476 (0.14%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 1476 (0.07%)
    0 / 82 (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 alkalosis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 1476 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A: Tafamidis (Parent and Extension Study) Cohort B: Tafamidis (Only in extension study) Cohort A: Placebo (Parent Study)/Tafamidis (Extension Study)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    152 / 170 (89.41%)
    1023 / 1476 (69.31%)
    76 / 82 (92.68%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    14 / 170 (8.24%)
    70 / 1476 (4.74%)
    20 / 82 (24.39%)
         occurrences all number
    16
    81
    24
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    5 / 170 (2.94%)
    10 / 1476 (0.68%)
    6 / 82 (7.32%)
         occurrences all number
    6
    11
    7
    Asthenia
         subjects affected / exposed
    13 / 170 (7.65%)
    54 / 1476 (3.66%)
    12 / 82 (14.63%)
         occurrences all number
    16
    59
    16
    Fatigue
         subjects affected / exposed
    19 / 170 (11.18%)
    78 / 1476 (5.28%)
    15 / 82 (18.29%)
         occurrences all number
    22
    82
    20
    Oedema peripheral
         subjects affected / exposed
    26 / 170 (15.29%)
    100 / 1476 (6.78%)
    18 / 82 (21.95%)
         occurrences all number
    30
    129
    27
    Peripheral swelling
         subjects affected / exposed
    9 / 170 (5.29%)
    22 / 1476 (1.49%)
    5 / 82 (6.10%)
         occurrences all number
    14
    23
    6
    Pyrexia
         subjects affected / exposed
    6 / 170 (3.53%)
    23 / 1476 (1.56%)
    5 / 82 (6.10%)
         occurrences all number
    9
    26
    6
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    3 / 170 (1.76%)
    21 / 1476 (1.42%)
    5 / 82 (6.10%)
         occurrences all number
    3
    21
    5
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    13 / 170 (7.65%)
    38 / 1476 (2.57%)
    5 / 82 (6.10%)
         occurrences all number
    15
    43
    6
    Dyspnoea
         subjects affected / exposed
    31 / 170 (18.24%)
    110 / 1476 (7.45%)
    18 / 82 (21.95%)
         occurrences all number
    41
    129
    30
    Cough
         subjects affected / exposed
    29 / 170 (17.06%)
    81 / 1476 (5.49%)
    18 / 82 (21.95%)
         occurrences all number
    42
    86
    24
    Pulmonary hypertension
         subjects affected / exposed
    2 / 170 (1.18%)
    8 / 1476 (0.54%)
    5 / 82 (6.10%)
         occurrences all number
    2
    8
    5
    Pleural effusion
         subjects affected / exposed
    23 / 170 (13.53%)
    58 / 1476 (3.93%)
    24 / 82 (29.27%)
         occurrences all number
    30
    72
    43
    Orthopnoea
         subjects affected / exposed
    6 / 170 (3.53%)
    11 / 1476 (0.75%)
    5 / 82 (6.10%)
         occurrences all number
    6
    11
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 170 (7.65%)
    57 / 1476 (3.86%)
    13 / 82 (15.85%)
         occurrences all number
    14
    61
    15
    Depression
         subjects affected / exposed
    8 / 170 (4.71%)
    23 / 1476 (1.56%)
    8 / 82 (9.76%)
         occurrences all number
    12
    23
    9
    Anxiety
         subjects affected / exposed
    7 / 170 (4.12%)
    28 / 1476 (1.90%)
    6 / 82 (7.32%)
         occurrences all number
    7
    29
    6
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 170 (1.18%)
    14 / 1476 (0.95%)
    5 / 82 (6.10%)
         occurrences all number
    2
    14
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 170 (1.76%)
    13 / 1476 (0.88%)
    6 / 82 (7.32%)
         occurrences all number
    3
    13
    6
    Weight decreased
         subjects affected / exposed
    10 / 170 (5.88%)
    32 / 1476 (2.17%)
    8 / 82 (9.76%)
         occurrences all number
    11
    41
    8
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    13 / 170 (7.65%)
    40 / 1476 (2.71%)
    5 / 82 (6.10%)
         occurrences all number
    13
    42
    6
    Fall
         subjects affected / exposed
    41 / 170 (24.12%)
    146 / 1476 (9.89%)
    34 / 82 (41.46%)
         occurrences all number
    85
    195
    48
    Limb injury
         subjects affected / exposed
    7 / 170 (4.12%)
    24 / 1476 (1.63%)
    5 / 82 (6.10%)
         occurrences all number
    7
    25
    6
    Skin abrasion
         subjects affected / exposed
    11 / 170 (6.47%)
    25 / 1476 (1.69%)
    6 / 82 (7.32%)
         occurrences all number
    11
    29
    8
    Skin laceration
         subjects affected / exposed
    12 / 170 (7.06%)
    46 / 1476 (3.12%)
    13 / 82 (15.85%)
         occurrences all number
    19
    56
    17
    Wound
         subjects affected / exposed
    4 / 170 (2.35%)
    13 / 1476 (0.88%)
    5 / 82 (6.10%)
         occurrences all number
    6
    13
    6
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    32 / 170 (18.82%)
    150 / 1476 (10.16%)
    17 / 82 (20.73%)
         occurrences all number
    37
    172
    19
    Cardiac failure
         subjects affected / exposed
    22 / 170 (12.94%)
    167 / 1476 (11.31%)
    9 / 82 (10.98%)
         occurrences all number
    28
    222
    17
    Pericardial effusion
         subjects affected / exposed
    6 / 170 (3.53%)
    8 / 1476 (0.54%)
    6 / 82 (7.32%)
         occurrences all number
    6
    8
    6
    Ventricular tachycardia
         subjects affected / exposed
    10 / 170 (5.88%)
    20 / 1476 (1.36%)
    9 / 82 (10.98%)
         occurrences all number
    12
    24
    14
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    24 / 170 (14.12%)
    97 / 1476 (6.57%)
    11 / 82 (13.41%)
         occurrences all number
    37
    104
    12
    Balance disorder
         subjects affected / exposed
    11 / 170 (6.47%)
    16 / 1476 (1.08%)
    4 / 82 (4.88%)
         occurrences all number
    12
    16
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 170 (8.24%)
    78 / 1476 (5.28%)
    12 / 82 (14.63%)
         occurrences all number
    15
    91
    12
    Leukocytosis
         subjects affected / exposed
    1 / 170 (0.59%)
    2 / 1476 (0.14%)
    5 / 82 (6.10%)
         occurrences all number
    2
    2
    6
    Eye disorders
    Cataract
         subjects affected / exposed
    10 / 170 (5.88%)
    24 / 1476 (1.63%)
    1 / 82 (1.22%)
         occurrences all number
    12
    30
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    5 / 170 (2.94%)
    20 / 1476 (1.36%)
    5 / 82 (6.10%)
         occurrences all number
    6
    20
    6
    Ascites
         subjects affected / exposed
    9 / 170 (5.29%)
    19 / 1476 (1.29%)
    4 / 82 (4.88%)
         occurrences all number
    11
    24
    5
    Constipation
         subjects affected / exposed
    18 / 170 (10.59%)
    117 / 1476 (7.93%)
    15 / 82 (18.29%)
         occurrences all number
    21
    126
    16
    Diarrhoea
         subjects affected / exposed
    15 / 170 (8.82%)
    97 / 1476 (6.57%)
    8 / 82 (9.76%)
         occurrences all number
    15
    110
    13
    Dysphagia
         subjects affected / exposed
    11 / 170 (6.47%)
    29 / 1476 (1.96%)
    7 / 82 (8.54%)
         occurrences all number
    11
    31
    10
    Nausea
         subjects affected / exposed
    17 / 170 (10.00%)
    48 / 1476 (3.25%)
    10 / 82 (12.20%)
         occurrences all number
    21
    53
    11
    Vomiting
         subjects affected / exposed
    10 / 170 (5.88%)
    30 / 1476 (2.03%)
    7 / 82 (8.54%)
         occurrences all number
    10
    32
    8
    Hepatobiliary disorders
    Congestive hepatopathy
         subjects affected / exposed
    1 / 170 (0.59%)
    6 / 1476 (0.41%)
    5 / 82 (6.10%)
         occurrences all number
    1
    6
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    17 / 170 (10.00%)
    36 / 1476 (2.44%)
    8 / 82 (9.76%)
         occurrences all number
    21
    36
    9
    Decubitus ulcer
         subjects affected / exposed
    3 / 170 (1.76%)
    9 / 1476 (0.61%)
    7 / 82 (8.54%)
         occurrences all number
    5
    9
    8
    Skin ulcer
         subjects affected / exposed
    10 / 170 (5.88%)
    25 / 1476 (1.69%)
    3 / 82 (3.66%)
         occurrences all number
    14
    30
    5
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    10 / 170 (5.88%)
    20 / 1476 (1.36%)
    13 / 82 (15.85%)
         occurrences all number
    11
    24
    15
    Acute kidney injury
         subjects affected / exposed
    15 / 170 (8.82%)
    54 / 1476 (3.66%)
    15 / 82 (18.29%)
         occurrences all number
    19
    64
    21
    Renal failure
         subjects affected / exposed
    11 / 170 (6.47%)
    10 / 1476 (0.68%)
    3 / 82 (3.66%)
         occurrences all number
    11
    10
    3
    Haematuria
         subjects affected / exposed
    7 / 170 (4.12%)
    47 / 1476 (3.18%)
    11 / 82 (13.41%)
         occurrences all number
    10
    49
    11
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    24 / 170 (14.12%)
    55 / 1476 (3.73%)
    9 / 82 (10.98%)
         occurrences all number
    41
    68
    17
    Osteoarthritis
         subjects affected / exposed
    12 / 170 (7.06%)
    20 / 1476 (1.36%)
    9 / 82 (10.98%)
         occurrences all number
    18
    21
    13
    Muscular weakness
         subjects affected / exposed
    11 / 170 (6.47%)
    19 / 1476 (1.29%)
    7 / 82 (8.54%)
         occurrences all number
    12
    20
    7
    Muscle spasms
         subjects affected / exposed
    14 / 170 (8.24%)
    53 / 1476 (3.59%)
    4 / 82 (4.88%)
         occurrences all number
    16
    55
    4
    Back pain
         subjects affected / exposed
    18 / 170 (10.59%)
    65 / 1476 (4.40%)
    12 / 82 (14.63%)
         occurrences all number
    23
    72
    12
    Arthralgia
         subjects affected / exposed
    29 / 170 (17.06%)
    78 / 1476 (5.28%)
    12 / 82 (14.63%)
         occurrences all number
    39
    91
    14
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 170 (5.29%)
    38 / 1476 (2.57%)
    6 / 82 (7.32%)
         occurrences all number
    11
    40
    9
    Cellulitis
         subjects affected / exposed
    16 / 170 (9.41%)
    51 / 1476 (3.46%)
    8 / 82 (9.76%)
         occurrences all number
    23
    56
    18
    Nasopharyngitis
         subjects affected / exposed
    9 / 170 (5.29%)
    30 / 1476 (2.03%)
    6 / 82 (7.32%)
         occurrences all number
    11
    31
    7
    Pneumonia
         subjects affected / exposed
    10 / 170 (5.88%)
    38 / 1476 (2.57%)
    12 / 82 (14.63%)
         occurrences all number
    15
    43
    14
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 170 (7.06%)
    53 / 1476 (3.59%)
    2 / 82 (2.44%)
         occurrences all number
    15
    56
    2
    Urinary tract infection
         subjects affected / exposed
    18 / 170 (10.59%)
    75 / 1476 (5.08%)
    16 / 82 (19.51%)
         occurrences all number
    27
    94
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 170 (5.29%)
    50 / 1476 (3.39%)
    8 / 82 (9.76%)
         occurrences all number
    10
    52
    9
    Dehydration
         subjects affected / exposed
    9 / 170 (5.29%)
    21 / 1476 (1.42%)
    4 / 82 (4.88%)
         occurrences all number
    12
    25
    7
    Fluid retention
         subjects affected / exposed
    9 / 170 (5.29%)
    19 / 1476 (1.29%)
    3 / 82 (3.66%)
         occurrences all number
    11
    23
    4
    Gout
         subjects affected / exposed
    18 / 170 (10.59%)
    113 / 1476 (7.66%)
    10 / 82 (12.20%)
         occurrences all number
    20
    134
    16
    Hyperglycaemia
         subjects affected / exposed
    2 / 170 (1.18%)
    10 / 1476 (0.68%)
    6 / 82 (7.32%)
         occurrences all number
    2
    10
    7
    Hyperkalaemia
         subjects affected / exposed
    5 / 170 (2.94%)
    35 / 1476 (2.37%)
    5 / 82 (6.10%)
         occurrences all number
    5
    35
    8
    Hyperuricaemia
         subjects affected / exposed
    9 / 170 (5.29%)
    32 / 1476 (2.17%)
    5 / 82 (6.10%)
         occurrences all number
    9
    33
    5
    Hypervolaemia
         subjects affected / exposed
    10 / 170 (5.88%)
    76 / 1476 (5.15%)
    11 / 82 (13.41%)
         occurrences all number
    12
    80
    17
    Hypokalaemia
         subjects affected / exposed
    23 / 170 (13.53%)
    61 / 1476 (4.13%)
    17 / 82 (20.73%)
         occurrences all number
    24
    75
    27
    Hyponatraemia
         subjects affected / exposed
    11 / 170 (6.47%)
    35 / 1476 (2.37%)
    13 / 82 (15.85%)
         occurrences all number
    13
    41
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2018
    Addition of a second cohort to enroll ATTR-CM diagnosed subjects who did not participate in parent study B3461028. Transition of all subjects to open label 61 mg dose (where available).

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Analyses based on CMA set for Cohort A of this study, data was combined from participants in study B3461028 (plus participants who died, discontinued) or not enrolled into the current study. Their data not included in other sections than endpoints.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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