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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-Controlled, Comparative Multicenter Phase 3 Study to Evaluate the Safety and Efficacy of BA058 (Abaloparatide) for Injection for Prevention of Fracture in Ambulatory Postmenopausal Women With Severe Osteoporosis and at Risk of Fracture

    Summary
    EudraCT number
    		 2010-022576-30
    Trial protocol
    		 EE   LT   DK   CZ   PL  
    Global end of trial date
    07 Oct 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    BA058-05-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01343004
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radius Health, Inc.
    Sponsor organisation address
    950 Winter Street, Waltham, MA, United States, 02451
    Public contact
    Associate Director, Clinical Operations, Radius Health, Inc., +1 6175514077, ncantacesso@radiuspharm.com
    Scientific contact
    VP, Oncology Clinical Development, Radius Health, Inc., +1 6175514086, mconlan@radiuspharm.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
    10 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the safety and efficacy of abaloparatide-subcutaneous (SC) 80 microgram (μg) when compared to placebo for prevention of new vertebral fracture in otherwise healthy ambulatory postmenopausal women at risk of osteoporotic fracture.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki in its revised edition (Seoul, 2008), the guidelines for current Good Clinical Practice (GCP) International Conference on Harmonization (ICH) (CPMP/ICH/135/95), the US Food and Drug Administration (FDA) Code of Federal Regulations (CFR) (21 CFR Parts 50, 54, 56 and 312), Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) regulations (Argentinean Investigators only), and all other applicable local regulatory and ethical requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 45
    Country: Number of subjects enrolled
    Brazil: 616
    Country: Number of subjects enrolled
    Czech Republic: 456
    Country: Number of subjects enrolled
    Denmark: 396
    Country: Number of subjects enrolled
    Estonia: 97
    Country: Number of subjects enrolled
    Hong Kong: 387
    Country: Number of subjects enrolled
    Lithuania: 84
    Country: Number of subjects enrolled
    Poland: 199
    Country: Number of subjects enrolled
    United States: 39
    Country: Number of subjects enrolled
    Romania: 144
    Worldwide total number of subjects
    2463
    EEA total number of subjects
    1376
    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)
    464
    From 65 to 84 years
    1997
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 5268 patients were screened and 2463 patients were enrolled in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo identical in appearance to BA058 study drug Placebo: Placebo 0 mcg subcutaneous daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo identical in appearance to BA058 study drug. Placebo 0 mcg subcutaneous daily

    Arm title
    		 BA058 80 mcg (abaloparatide)
    Arm description
    		 BA058 80 mcg: BA058 80 mcg subcutaneous daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    BA058 80 mcg (abaloparatide)
    Investigational medicinal product code
    Other name
    abaloparatide, Abaloparatide-SC
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    BA058 80 mcg subcutaneous daily

    Arm title
    		 Teriparatide
    Arm description
    		 Blinded until after randomization, then open-label teriparatide: teriparatide 20 mcg subcutaneous daily
    Arm type
    		 Active comparator

    Investigational medicinal product name
    teriparatide
    Investigational medicinal product code
    Other name
    Forteo, Forsteo
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Blinded until after randomization, then open-label. Teriparatide 20 mcg subcutaneous daily

    Number of subjects in period 1
    		Placebo BA058 80 mcg (abaloparatide) Teriparatide
    Started
    821
    824
    818
    Completed
    637
    606
    658
    Not completed
    184
    218
    160
         Significant deterioration from baseline of BMD
    12
    1
    1
         Adverse event, serious fatal
    5
    3
    3
         Serious Intercurrent Illness
    -
    4
    5
         Hypersensitivity: aloparatide/placebo/teriparatide
    1
    -
    -
         Patient died during the study
    5
    3
    2
         Other than Specified
    6
    5
    3
         Hypercalcemia or Hypercalciuria
    -
    1
    1
         Refusal of Treatment
    33
    31
    19
         Administrative Reasons
    -
    1
    -
         Consent withdrawn by subject
    48
    47
    45
         Adverse event, non-fatal
    48
    86
    50
         Non-compliance
    10
    6
    9
         Treatment related SAE
    -
    -
    2
         Lost to follow-up
    5
    15
    10
         Protocol deviation
    4
    4
    5
         Inability to Complete Study Procedures
    7
    11
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo identical in appearance to BA058 study drug Placebo: Placebo 0 mcg subcutaneous daily

    Reporting group title
    BA058 80 mcg (abaloparatide)
    Reporting group description
    		 BA058 80 mcg: BA058 80 mcg subcutaneous daily

    Reporting group title
    Teriparatide
    Reporting group description
    		 Blinded until after randomization, then open-label teriparatide: teriparatide 20 mcg subcutaneous daily

    Reporting group values
    		 Placebo BA058 80 mcg (abaloparatide) Teriparatide Total
    Number of subjects
    		 821 824 818 2463
    Age categorical
    Units: Subjects
        <65 years
    		 161 152 151 464
        65 to <75 years
    		 512 517 503 1532
        >=75 years
    		 148 155 164 467
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.7 ( 6.5 ) 68.9 ( 6.5 ) 68.8 ( 6.6 ) -
    Gender, Male/Female
    Units:
        Female
    		 821 824 818 2463
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo identical in appearance to BA058 study drug Placebo: Placebo 0 mcg subcutaneous daily

    Reporting group title
    BA058 80 mcg (abaloparatide)
    Reporting group description
    		 BA058 80 mcg: BA058 80 mcg subcutaneous daily

    Reporting group title
    Teriparatide
    Reporting group description
    		 Blinded until after randomization, then open-label teriparatide: teriparatide 20 mcg subcutaneous daily

    Primary: Number of Participants with New Vertebral Fractures at 18 Months

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    End point title
    		 Number of Participants with New Vertebral Fractures at 18 Months
    End point description
    Modified intent-to-treat (MITT) population included all patients with pre-treatment and end-of-treatment evaluable radiologic assessment (spine X-ray).
    End point type
    Primary
    End point timeframe
    18 months
    End point values
    		 Placebo BA058 80 mcg (abaloparatide) Teriparatide
    Number of subjects analysed
    711
    690
    717
    Units: participants
    30
    4
    6
    Statistical analysis title
    		 Placebo versus BA058 80 mcg (Abaloparatide)
    Comparison groups
    Placebo v BA058 80 mcg (abaloparatide)
    Number of subjects included in analysis
    1401
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Placebo versus Teriparatide
    Comparison groups
    Placebo v Teriparatide
    Number of subjects included in analysis
    1428
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percent Change in Bone Mineral Density (BMD) of Lumbar Spine from Baseline to 18 Months

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    End point title
    		 Percent Change in Bone Mineral Density (BMD) of Lumbar Spine from Baseline to 18 Months
    End point description
    Intent-to-treat population included all patients who were randomized into the study by assigning the randomized study medication kit on Day 1. Baseline BMD data were missing for some patients; the method of last observation carried forward (LOCF) was used to impute missing data.
    End point type
    Secondary
    End point timeframe
    Baseline and 18 months
    End point values
    		 Placebo BA058 80 mcg (abaloparatide) Teriparatide
    Number of subjects analysed
    821
    823
    818
    Units: percent change from baseline
        arithmetic mean (standard deviation)
    0.48 ( 3.82 )
    9.20 ( 7.54 )
    9.12 ( 6.28 )
    Statistical analysis title
    		 Placebo versus BA058 80 mcg (Abaloparatide)
    Comparison groups
    Placebo v BA058 80 mcg (abaloparatide)
    Number of subjects included in analysis
    1644
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 BA058 80 mcg (Abaloparatide) versus Teriparatide
    Comparison groups
    BA058 80 mcg (abaloparatide) v Teriparatide
    Number of subjects included in analysis
    1641
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8155
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Placebo versus Teriparatide
    Comparison groups
    Placebo v Teriparatide
    Number of subjects included in analysis
    1639
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Percent Change in Bone Mineral Density (BMD) of Total Hip from Baseline to Month 18

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    End point title
    		 Percent Change in Bone Mineral Density (BMD) of Total Hip from Baseline to Month 18
    End point description
    Intent-to-treat population included all patients who were randomized into the study by assigning the randomized study medication kit on Day 1. Baseline BMD data were missing for some patients; the method of LOCF was used to impute missing data.
    End point type
    Secondary
    End point timeframe
    Baseline and 18 months
    End point values
    		 Placebo BA058 80 mcg (abaloparatide) Teriparatide
    Number of subjects analysed
    820
    822
    818
    Units: percent change
        arithmetic mean (standard deviation)
    -0.08 ( 2.77 )
    3.44 ( 3.51 )
    2.81 ( 3.33 )
    Statistical analysis title
    		 Placebo versus BA058 80 mcg (Abaloparatide)
    Comparison groups
    Placebo v BA058 80 mcg (abaloparatide)
    Number of subjects included in analysis
    1642
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Placebo versus Teriparatide
    Comparison groups
    Placebo v Teriparatide
    Number of subjects included in analysis
    1638
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 BA058 80 mcg (Abaloparatide) versus Teriparatide
    Comparison groups
    BA058 80 mcg (abaloparatide) v Teriparatide
    Number of subjects included in analysis
    1640
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Percent Change in Bone Mineral Density (BMD) of Femoral Neck from Baseline to Month 18

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    End point title
    		 Percent Change in Bone Mineral Density (BMD) of Femoral Neck from Baseline to Month 18
    End point description
    Intent-to-treat population included all patients who were randomized into the study by assigning the randomized study medication kit on Day 1. Baseline BMD data were missing for some patients; the method of LOCF was used to impute missing data.
    End point type
    Secondary
    End point timeframe
    Baseline and 18 months
    End point values
    		 Placebo BA058 80 mcg (abaloparatide) Teriparatide
    Number of subjects analysed
    820
    822
    818
    Units: percent change
        arithmetic mean (standard deviation)
    -0.44 ( 3.57 )
    2.90 ( 4.21 )
    2.26 ( 3.57 )
    Statistical analysis title
    		 Placebo versus BA058 80 mcg (Abaloparatide)
    Comparison groups
    Placebo v BA058 80 mcg (abaloparatide)
    Number of subjects included in analysis
    1642
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Placebo versus Teriparatide
    Comparison groups
    Placebo v Teriparatide
    Number of subjects included in analysis
    1638
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 BA058 80 mcg (Abaloparatide) versus Teriparatide
    Comparison groups
    BA058 80 mcg (abaloparatide) v Teriparatide
    Number of subjects included in analysis
    1640
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0004
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Number of Participants with Non-vertebral Fractures at 18 Months

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    End point title
    		 Number of Participants with Non-vertebral Fractures at 18 Months
    End point description
    Intent-to-treat population included all patients who were randomized into the study by assigning the randomized study medication kit on Day 1.
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 Placebo BA058 80 mcg (abaloparatide) Teriparatide
    Number of subjects analysed
    821
    824
    818
    Units: Participants
    33
    18
    24
    Statistical analysis title
    		 Placebo versus BA058 80 mcg (Abaloparatide)
    Comparison groups
    Placebo v BA058 80 mcg (abaloparatide)
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0318
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Placebo versus Teriparatide
    Comparison groups
    Placebo v Teriparatide
    Number of subjects included in analysis
    1639
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2304
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 BA058 80 mcg (Abaloparatide) versus Teriparatide
    Comparison groups
    BA058 80 mcg (abaloparatide) v Teriparatide
    Number of subjects included in analysis
    1642
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3361
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Number of Treatment-Emergent Adverse Events Associated with Hypercalcemia at 18 Months

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    End point title
    		 Number of Treatment-Emergent Adverse Events Associated with Hypercalcemia at 18 Months
    End point description
    Safety population included all patients who received 1 or more doses of study medication.
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 Placebo BA058 80 mcg (abaloparatide) Teriparatide
    Number of subjects analysed
    820
    822
    818
    Units: Hypercalcemic events
    5
    15
    34
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 18 months
    Adverse event reporting additional description
    Individual number of occurrences (events) are not available for this study. Therefore, the number of subjects exposed per preferred term are reported in the field for the number of occurrences (events).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo identical in appearance to BA058 study drug Placebo: Placebo 0 mcg subcutaneous daily

    Reporting group title
    Teriparatide
    Reporting group description
    		 Blinded until after randomization, then open-label teriparatide: teriparatide 20 mcg subcutaneous daily

    Reporting group title
    BA058 80 mcg (abaloparatide)
    Reporting group description
    		 BA058 80 mcg: BA058 80 mcg subcutaneous daily

    Serious adverse events
    		 Placebo Teriparatide BA058 80 mcg (abaloparatide)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    90 / 820 (10.98%)
    82 / 818 (10.02%)
    80 / 822 (9.73%)
         number of deaths (all causes)
    5
    3
    3
         number of deaths resulting from adverse events
    5
    3
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 820 (0.12%)
    6 / 818 (0.73%)
    3 / 822 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer stage II
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melanocytic naevus
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic neoplasm
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Angiolipoma
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         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 neoplasm of thyroid gland
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct adenocarcinoma
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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 neoplasm
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         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 leukaemia
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric neoplasm
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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 carcinoma
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         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 adenocarcinoma
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Myeloproliferative disorder
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         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 / 820 (0.00%)
    2 / 818 (0.24%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Vascular disorders
    Intermittent claudication
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 820 (0.24%)
    2 / 818 (0.24%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colporrhaphy
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary angioplasty
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint arthroplasty
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    0 / 822 (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
    Osteosynthesis
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectocele repair
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Removal of internal fixation
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Toe operation
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         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
    Chest pain
         subjects affected / exposed
    2 / 820 (0.24%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    General physical health deterioration
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (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
    Sudden death
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    2 / 820 (0.24%)
    1 / 818 (0.12%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 820 (0.00%)
    3 / 818 (0.37%)
    0 / 822 (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
    Uterine polyp
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    0 / 822 (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
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus polyp
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Allergic bronchitis
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         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 mass
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchoscopy
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Liver function test abnormal
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    2 / 820 (0.24%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative hernia
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 820 (0.00%)
    2 / 818 (0.24%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    2 / 820 (0.24%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Femur fracture
         subjects affected / exposed
    3 / 820 (0.37%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Hand fracture
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Lower limb fracture
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    3 / 820 (0.37%)
    2 / 818 (0.24%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Radius fracture
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Tibia fracture
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    0 / 822 (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
    Ulna fracture
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Wrist fracture
         subjects affected / exposed
    0 / 820 (0.00%)
    2 / 818 (0.24%)
    0 / 822 (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
    Myocardial ischaemia
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         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 myocardial infarction
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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 unstable
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Cardiomyopathy
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve stenosis
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         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 bradycardia
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Myocardial infarction
         subjects affected / exposed
    2 / 820 (0.24%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    2 / 820 (0.24%)
    2 / 818 (0.24%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radicular syndrome
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarchnoid haemorrhage
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    0 / 822 (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
    Dizziness
         subjects affected / exposed
    1 / 820 (0.12%)
    2 / 818 (0.24%)
    0 / 822 (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
    Ischaemic stroke
         subjects affected / exposed
    3 / 820 (0.37%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Malculopathy
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal artery occulusion
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    2 / 820 (0.24%)
    1 / 818 (0.12%)
    0 / 822 (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
    Gastrointestinal disorders
    Gastric Ulcer
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 820 (0.37%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Change of bowel habit
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Diverticulum
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    0 / 822 (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
    Enterocele
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         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 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         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
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Inguinal hernia
         subjects affected / exposed
    2 / 820 (0.24%)
    0 / 818 (0.00%)
    0 / 822 (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
    Large intestine polyp
         subjects affected / exposed
    2 / 820 (0.24%)
    0 / 818 (0.00%)
    0 / 822 (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
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    3 / 822 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Biliary dyskinesia
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    0 / 822 (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
    Skin and subcutaneous tissue disorders
    Dermititis allergic
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Drug eruption
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (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
    Hypersensitivity vasculitis
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 820 (0.12%)
    2 / 818 (0.24%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid cyst
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 820 (0.12%)
    3 / 818 (0.37%)
    3 / 822 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 820 (0.37%)
    1 / 818 (0.12%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    0 / 822 (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
    Arthritis reactive
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spine stenosis
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Spondylisthesis
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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
    Dengue fever
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Helicobacter infection
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (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 tract infection
         subjects affected / exposed
    1 / 820 (0.12%)
    1 / 818 (0.12%)
    0 / 822 (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
    Viral infection
         subjects affected / exposed
    1 / 820 (0.12%)
    0 / 818 (0.00%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 820 (0.00%)
    0 / 818 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 820 (0.00%)
    1 / 818 (0.12%)
    0 / 822 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Teriparatide BA058 80 mcg (abaloparatide)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    447 / 820 (54.51%)
    456 / 818 (55.75%)
    492 / 822 (59.85%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    52 / 820 (6.34%)
    41 / 818 (5.01%)
    59 / 822 (7.18%)
         occurrences all number
    52
    41
    59
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 820 (0.37%)
    13 / 818 (1.59%)
    42 / 822 (5.11%)
         occurrences all number
    3
    13
    42
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    50 / 820 (6.10%)
    59 / 818 (7.21%)
    82 / 822 (9.98%)
         occurrences all number
    50
    59
    82
    Headache
         subjects affected / exposed
    49 / 820 (5.98%)
    51 / 818 (6.23%)
    62 / 822 (7.54%)
         occurrences all number
    49
    51
    62
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    42 / 820 (5.12%)
    34 / 818 (4.16%)
    36 / 822 (4.38%)
         occurrences all number
    42
    34
    36
    Nausea
         subjects affected / exposed
    25 / 820 (3.05%)
    42 / 818 (5.13%)
    68 / 822 (8.27%)
         occurrences all number
    25
    42
    68
    Renal and urinary disorders
    Hypercalciuria
         subjects affected / exposed
    74 / 820 (9.02%)
    102 / 818 (12.47%)
    93 / 822 (11.31%)
         occurrences all number
    74
    102
    93
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    80 / 820 (9.76%)
    70 / 818 (8.56%)
    71 / 822 (8.64%)
         occurrences all number
    80
    70
    71
    Back pain
         subjects affected / exposed
    81 / 820 (9.88%)
    58 / 818 (7.09%)
    69 / 822 (8.39%)
         occurrences all number
    81
    58
    69
    Pain in extremity
         subjects affected / exposed
    49 / 820 (5.98%)
    42 / 818 (5.13%)
    40 / 822 (4.87%)
         occurrences all number
    49
    42
    40
    Infections and infestations
    Influenza
         subjects affected / exposed
    39 / 820 (4.76%)
    34 / 818 (4.16%)
    52 / 822 (6.33%)
         occurrences all number
    39
    34
    52
    Nasopharyngitis
         subjects affected / exposed
    66 / 820 (8.05%)
    52 / 818 (6.36%)
    48 / 822 (5.84%)
         occurrences all number
    66
    52
    48
    Upper respiratory tract infection
         subjects affected / exposed
    63 / 820 (7.68%)
    73 / 818 (8.92%)
    68 / 822 (8.27%)
         occurrences all number
    63
    73
    68
    Urinary tract infection
         subjects affected / exposed
    38 / 820 (4.63%)
    41 / 818 (5.01%)
    43 / 822 (5.23%)
         occurrences all number
    38
    41
    43

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2011
    The protocol was amended to: • modify the “Inclusion Criteria” section of the synopsis to clarify that patients who had participated in a clinical study of any novel unapproved medication in the past 12 months would be excluded from participation in BA058-005-03 unless they had received placebo. • to allow patients who might have been considered for the study but were ineligible because of recent or current use of thiazides to be considered for enrollment after activation of this amendment • increase the time allowed for screening procedures to facilitate sample transport and reporting, and repeat samples, and • provide clarification on a number of questions arising from participating sites. These modifications did not impact the conduct of the study, but rather clarified certain aspects of the study conduct, such as − to clarify the timing of post-dose assessment of serum calcium levels, − to allow retesting of serum 25 hydroxy vitamin D and PTH levels after vitamin D supplementation − to clarify that albumin-corrected calcium will be used for assessment of serum calcium, both in safety and PD assessments, and − to clarify that ionized calcium levels can be considered in assessing eligibility.
    05 Jul 2012
    The following modifications were made to the protocol: • Pre- and post-study renal CT scans in patients in selected centers was added; the previous version of the protocol required only post-study renal CT scans. • A bone biopsy was added for teriparatide patients; the previous version of the protocol required bone biopsies for patients in the abaloparatide and placebo arms. • A modification of the description of the Extension Study (Protocol BA058-05-005 [NCT01657162]) was made. The revised Study BA058-05-005 offered patients receiving abaloparatide/placebo treatment an additional six months of osteoporosis care, including recommended treatment with alendronate, as appropriate. The previous version of the Extension Study called for an additional six months of abaloparatide followed by 24 months of treatment with a bisphosphonate. • A paragraph was added to describe the results of an ongoing rat carcinogenicity study with abaloparatide. • A requirement was added that subjects who experience a clinical fracture during the study and elect to continue to participate would need to provide re-consent prior to continuing in the study.
    31 Mar 2014
    The following modifications were made to the protocol: • The name of BA058 was changed to abaloparatide throughout the document. • A new Sponsor Medical Monitor/Study Safety Officer was added. • Clarifications were made to more accurately describe the sequence of procedures in the protocol. • Modifications were made to more clearly define how incident vertebral and nonvertebral fractures were diagnosed. • Modifications were made to clarify that the hypercalcemia algorithm is based on pre- not post-dose serum calcium. • Modifications were made to clarify the patient populations to be analyzed. • Clarification of the definition of a protocol violation was added to align the protocol with Radius’ Protocol Deviation/Violation Procedure Manual (Version 3.0, 1 October 2012). • Clarification of the definition of a protocol deviation was added to align the protocol with Radius’ Protocol Deviation/Violation Procedure Manual (Version 3.0, 1 October 2012).

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

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