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    Clinical Trial Results:
    A Multicenter, International, Randomized, Double-blind, Alendronate-controlled Study to Determine the Efficacy and Safety of Romosozumab in the Treatment of Postmenopausal Women With Osteoporosis

    Summary
    EudraCT number
    		 2011-003142-41
    Trial protocol
    		 IT   LT   FI   PL   BE   CZ   ES   EE   GR   DE   GB   SE   AT   DK   LV   NO   NL   HU   IE   SK   BG  
    Global end of trial date
    29 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jul 2018
    First version publication date
    15 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20110142
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01631214
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    29 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the effect of romosozumab treatment for 12 months followed by alendronate treatment compared with alendronate treatment alone on the subject incidence of: - clinical fracture (nonvertebral fracture and clinical vertebral fracture); and - new vertebral fracture in postmenopausal women with osteoporosis.
    Protection of trial subjects
    This study was conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable Food and Drug Administration (FDA) or local regulations/guidelines. The study protocol, subject information, and informed consent form (ICF) were reviewed and approved by the independent ethics committee (IEC) or institutional review board (IRB) for each study center. Before any study procedures were performed or any investigational products were administered, the investigator obtained written informed consent from each subject after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 2012
    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
    Slovakia: 16
    Country: Number of subjects enrolled
    South Africa: 154
    Country: Number of subjects enrolled
    Spain: 38
    Country: Number of subjects enrolled
    Sweden: 28
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    United Kingdom: 76
    Country: Number of subjects enrolled
    United States: 57
    Country: Number of subjects enrolled
    Argentina: 108
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Austria: 37
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Brazil: 295
    Country: Number of subjects enrolled
    Bulgaria: 112
    Country: Number of subjects enrolled
    Canada: 40
    Country: Number of subjects enrolled
    Chile: 24
    Country: Number of subjects enrolled
    Colombia: 634
    Country: Number of subjects enrolled
    Czech Republic: 282
    Country: Number of subjects enrolled
    Denmark: 73
    Country: Number of subjects enrolled
    Dominican Republic: 29
    Country: Number of subjects enrolled
    Estonia: 51
    Country: Number of subjects enrolled
    Finland: 13
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Greece: 33
    Country: Number of subjects enrolled
    Guatemala: 75
    Country: Number of subjects enrolled
    Hong Kong: 249
    Country: Number of subjects enrolled
    Hungary: 142
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 76
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Latvia: 43
    Country: Number of subjects enrolled
    Lithuania: 50
    Country: Number of subjects enrolled
    Mexico: 117
    Country: Number of subjects enrolled
    Netherlands: 25
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    Norway: 35
    Country: Number of subjects enrolled
    Peru: 119
    Country: Number of subjects enrolled
    Poland: 704
    Country: Number of subjects enrolled
    Romania: 23
    Country: Number of subjects enrolled
    Russian Federation: 157
    Worldwide total number of subjects
    4093
    EEA total number of subjects
    1965
    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)
    479
    From 65 to 84 years
    3286
    85 years and over
    328

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 270 centers in 41 countries globally from 04 May 2012 to 29 June 2017.

    Pre-assignment
    Screening details
    		 Participants were randomized in a 1:1 ratio to receive romosozumab or alendronate for 12 months. Randomization was stratified by age (< 75 vs. ≥ 75 years). After completion of the double-blind trial period, all participants received open-label alendronate until the end of the trial, with blinding to the initial treatment assignment maintained.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alendronate/Alendronate
    Arm description
    		 Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Alendronate
    Investigational medicinal product code
    Other name
    Fosamax®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alendronate 70-mg tablet taken once a week

    Investigational medicinal product name
    Placebo to Romosozumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once a month during the double-blind treatment phase.

    Arm title
    		 Romosozumab/Alendronate
    Arm description
    		 Participants received 210 romosozumab mg subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo to Alendronate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablet taken once a week during the double-blind treatment phase.

    Investigational medicinal product name
    Alendronate
    Investigational medicinal product code
    Other name
    Fosamax®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alendronate 70 mg tablet taken once a week during the open-label treatment phase.

    Investigational medicinal product name
    Romosozumab
    Investigational medicinal product code
    AMG 785
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Romosozumab 210 mg administered by subcutaneous injection once a month during the double-blind treatment phase.

    Number of subjects in period 1
    		Alendronate/Alendronate Romosozumab/Alendronate
    Started
    2047
    2046
    Received Double-blind Treatment
    2040
    2038
    Completed Double-blind Period
    1823
    1831
    Completed
    1503
    1523
    Not completed
    544
    523
         Consent withdrawn by subject
    276
    290
         Adverse event, non-fatal
    45
    45
         Administrative decision
    1
    -
         Death
    113
    106
         Other
    22
    19
         Protocol deviation
    4
    3
         Lost to follow-up
    54
    40
         Ineligibility determined
    5
    2
         Noncompliance
    16
    15
         Requirement for alternative therapy
    8
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alendronate/Alendronate
    Reporting group description
    		 Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.

    Reporting group title
    Romosozumab/Alendronate
    Reporting group description
    		 Participants received 210 romosozumab mg subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.

    Reporting group values
    		 Alendronate/Alendronate Romosozumab/Alendronate Total
    Number of subjects
    		 2047 2046 4093
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 240 239 479
        From 65-84 years
    		 1642 1644 3286
        85 years and over
    		 165 163 328
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.2 ± 7.5 74.4 ± 7.5 -
    Gender Categorical
    Units: Subjects
        Female
    		 2047 2046 4093
        Male
    		 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 7 5 12
        Asian
    		 149 137 286
        Black or African American
    		 23 19 42
        Native Hawaiian or Other Pacific Islander
    		 2 0 2
        White
    		 1415 1447 2862
        Multiple
    		 4 2 6
        Other
    		 446 436 882
        Missing
    		 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 662 631 1293
        Not Hispanic or Latino
    		 1385 1415 2800
    Age Strata per Randomization
    Units: Subjects
        < 75 years
    		 976 973 1949
        ≥ 75 years
    		 1071 1073 2144
    Severe Vertebral Fracture
    A subject had a prevalent vertebral fracture if any vertebra from T4 to L4 had a grade of 3 at baseline based on an assessment of spinal radiographs using Genant Semiquantitative Scoring Method. Otherwise, a subject was considered absence of severe vertebral fracture at baseline. vertebral fracture at baseline.
    Units: Subjects
        Presence
    		 1321 1369 2690
        Absence
    		 726 677 1403
    Total Hip Bone Mineral Density (BMD) T-score
    BMD was measured using dual-energy x-ray absorptiometry (DXA). The T-score is a comparison of a person's bone density with that of a healthy 30-year-old of the same sex. Lower scores (more negative) mean lower bone density: A T-score of -2.5 or lower qualifies as osteoporosis and a T-score of -1.0 to -2.5 signifies osteopenia, meaning below-normal bone density without full osteoporosis.
    Units: Subjects
        ≤ -2.5
    		 1384 1356 2740
        > -2.5
    		 662 690 1352
        Missing
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Alendronate/Alendronate
    Reporting group description
    		 Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.

    Reporting group title
    Romosozumab/Alendronate
    Reporting group description
    		 Participants received 210 romosozumab mg subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.

    Primary: Percentage of Participants with New Vertebral Fractures Through Month 24

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    End point title
    		 Percentage of Participants with New Vertebral Fractures Through Month 24
    End point description
    New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant semiquantitative scoring method based on assessment of x-rays according to the following scale: • Grade 0 (Normal) = no fracture; • Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); • Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; • Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. The analysis was conducted in randomized participants with a baseline and ≥ 1 post-baseline evaluation of vertebral fracture at or before 24 months and includes participants who had vertebrae with missing Genant semiquantitative scores at baseline and whose first post-baseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.
    End point type
    Primary
    End point timeframe
    24 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1834
    1825
    Units: percentage of participants
        number (not applicable)
    8.0
    4.1
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3659
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [1] - The primary endpoints were tested at the 5% level (2-sided), accounting for multiplicity using the Hochberg procedure. If the larger of the 2 P-values was significant at the 0.05 level (2-sided), the statistical testing continued to the secondary endpoint in the testing sequence.
    [2] - Based on logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline. The standard error (SE) represents the standard error of log(odds ratio).
    Statistical analysis title
    		 Risk Ratio
    Statistical analysis description
    The risk ratio (ratio of proportions, Romosozumab over Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T score at the total hip (≤ -2.5, > -2.5). SE represents the standard error of log(risk ratio).
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3659
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Statistical analysis title
    		 Absolute Risk Reduction
    Statistical analysis description
    The absolute risk reduction (difference in proportions, alendronate – romosozumab) based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline.
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3659
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Absolute risk reduction
    Point estimate
    4.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 5.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.78

    Primary: Percentage of Participants with a Clinical Fracture at the Primary Analysis

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    End point title
    		 Percentage of Participants with a Clinical Fracture at the Primary Analysis
    End point description
    Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded. The analysis was conducted in all randomized participants. Missing values for clinical vertebral fractures were imputed using last observation carried forward.
    End point type
    Primary
    End point timeframe
    The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    13.0
    9.7
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Notes
    [3] - The primary endpoints were tested at the 5% level (2-sided), accounting for multiplicity using the Hochberg procedure. If the larger of the 2 P-values was significant at the 0.05 level (2-sided), the statistical testing continued to the secondary endpoint in the testing sequence.
    [4] - Based on a Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with a Nonvertebral Fracture at the Primary Analysis

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    End point title
    		 Percentage of Participants with a Nonvertebral Fracture at the Primary Analysis
    End point description
    A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. The analysis was conducted in all randomized participants.
    End point type
    Secondary
    End point timeframe
    The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    10.6
    8.7
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.04 [6]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 0.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [5] - If the 2 primary endpoints and the specified BMD secondary endpoints were all significant, the nonvertebral fracture at the primary analysis was evaluated based on a 1-sided test (overall α=0.025) determined by the Lan-DeMets alpha spending function that approximates a Pocock boundary, 0.0233 (1-sided). The adjusted 2-sided p-value is reported.
    [6] - Based on a Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with any Fracture at the Primary Analysis

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    End point title
    		 Percentage of Participants with any Fracture at the Primary Analysis
    End point description
    All fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures. The analysis was conducted in all randomized participants.
    End point type
    Secondary
    End point timeframe
    The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    19.1
    13.0
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001 [8]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 0.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08
    Notes
    [7] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [8] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with a New or Worsening Vertebral Fracture Through Month 24

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    End point title
    		 Percentage of Participants with a New or Worsening Vertebral Fracture Through Month 24
    End point description
    A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4. The analysis was conducted in randomized participants with a baseline and ≥ 1 post-baseline evaluation of vertebral fracture at or before 24 months and includes participants who had vertebrae with missing Genant semiquantitative scores at baseline and whose first post-baseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1834
    1825
    Units: percentage of participants
        number (not applicable)
    9.2
    4.8
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3659
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.001 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Notes
    [9] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [10] - Based on a logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline; p-value based on score test. SE represents the standard error of log(odds ratio).
    Statistical analysis title
    		 Absolute Risk Reduction
    Statistical analysis description
    The absolute risk reduction (difference in proportions, Alendronate – Romosozumab) based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline.
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3659
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Absolute Risk Reduction
    Point estimate
    4.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.8
         upper limit
    		 6.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.84
    Statistical analysis title
    		 Risk Ratio
    Statistical analysis description
    The risk ratio (ratio of proportions, Romosozumab over Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T score at the total hip (≤ -2.5, > -2.5). SE represents the standard error of log(risk ratio).
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3659
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13

    Secondary: Percentage of Participants with a Major Nonvertebral Fracture at the Primary Analysis

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    End point title
    		 Percentage of Participants with a Major Nonvertebral Fracture at the Primary Analysis
    End point description
    A major nonvertebral fracture was a subset of nonvertebral fractures including pelvis, distal femur (ie, femur excluding hip), proximal tibia (ie, tibia excluding ankle), ribs, proximal humerus (ie, humerus excluding elbow), forearm, and hip. The analysis was conducted in all randomized participants.
    End point type
    Secondary
    End point timeframe
    The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    9.6
    7.1
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.004 [12]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [11] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [12] - Based on a Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with a Hip Fracture at the Primary Analysis

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    End point title
    		 Percentage of Participants with a Hip Fracture at the Primary Analysis
    End point description
    Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter. The analysis was conducted in all randomized participants.
    End point type
    Secondary
    End point timeframe
    The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    3.2
    2.0
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.015 [14]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [13] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [14] - Based on a Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with Multiple New or Worsening Vertebral Fractures Through Month 24

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    End point title
    		 Percentage of Participants with Multiple New or Worsening Vertebral Fractures Through Month 24
    End point description
    A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4. A participant had multiple new or worsening vertebral fractures when there were ≥ 2 vertebrae from T4 to L4 with ≥ 1 grade increase from the previous grade. The multiple new or worsening vertebral fractures need not have occurred at the same visit. The analysis was conducted in randomized participants with a baseline and ≥ 1 post-baseline evaluation of vertebral fracture at or before 24 months and includes participants who had vertebrae with missing Genant semiquantitative scores at baseline and whose first post-baseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1834
    1825
    Units: percentage of participants
        number (not applicable)
    2.5
    1.3
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3659
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.008 [16]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [15] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [16] - Based on logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline. SE represents the standard error of log(odds ratio).
    Statistical analysis title
    		 Risk Ratio
    Statistical analysis description
    The risk ratio (ratio of proportions, Romosozumab over Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T score at the total hip (≤ -2.5, > -2.5). SE represents the standard error of log(risk ratio).
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3659
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 0.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Statistical analysis title
    		 Absolute Risk Reduction
    Statistical analysis description
    The absolute risk reduction (difference in proportions, alendronate – romosozumab) based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline.
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3659
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Absolute risk reduction
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.45

    Secondary: Percentage of Participants with a Clinical Fracture Through Month 24

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    End point title
    		 Percentage of Participants with a Clinical Fracture Through Month 24
    End point description
    Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded. The analysis was conducted in all randomized participants. Missing values for clinical vertebral fractures were imputed using last observation carried forward.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    9.6
    7.1
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.005 [18]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [17] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [18] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with a Nonvertebral Fracture Through Month 24

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    End point title
    		 Percentage of Participants with a Nonvertebral Fracture Through Month 24
    End point description
    A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. The analysis was conducted in all randomized participants.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    7.8
    6.3
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.074 [20]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [19] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [20] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with a Hip Fracture Through Month 24

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    End point title
    		 Percentage of Participants with a Hip Fracture Through Month 24
    End point description
    Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter. The analysis was conducted in all randomized participants.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    2.1
    1.5
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.17 [22]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.24
    Notes
    [21] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [22] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with a Clinical Vertebral Fracture Through Month 24

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    End point title
    		 Percentage of Participants with a Clinical Vertebral Fracture Through Month 24
    End point description
    A clinical vertebral fracture is a new or worsening vertebral fracture assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms of back pain indicative of a fracture, regardless of trauma severity or whether it is pathologic. The analysis was conducted in all randomized participants. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    2.1
    0.9
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.001 [24]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28
    Notes
    [23] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [24] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log(hazards ratio).

    Secondary: Percentage of Participants with a Clinical Fracture Through Month 12

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    End point title
    		 Percentage of Participants with a Clinical Fracture Through Month 12
    End point description
    Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded. The analysis was conducted in all randomized participants. Missing values for clinical vertebral fractures were imputed using last observation carried forward.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    5.4
    3.9
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.027 [26]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [25] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [26] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with New Vertebral Fractures Through Month 12

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    End point title
    		 Percentage of Participants with New Vertebral Fractures Through Month 12
    End point description
    New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant semiquantitative scoring method based on assessment of x-rays according to the following scale: • Grade 0 (Normal) = no fracture; • Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); • Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; • Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. The analysis was conducted in randomized participants with a baseline and ≥ 1 post-baseline evaluation of vertebral fracture at or before 12 months and includes participants who had vertebrae with missing Genant semiquantitative scores at baseline and whose first post-baseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1703
    1696
    Units: percentage of participants
        number (not applicable)
    5.0
    3.2
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.008 [28]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.18
    Notes
    [27] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [28] - Based on logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline. SE represents the standard error of log (odds ratio).
    Statistical analysis title
    		 Risk Ratio
    Statistical analysis description
    The risk ratio (ratio of proportions, Romosozumab over Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T score at the total hip (≤ -2.5, > -2.5). SE represents the standard error of log (risk ratio).
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Statistical analysis title
    		 Absolute Risk Reduction
    Statistical analysis description
    The absolute risk reduction (difference in proportions, alendronate – romosozumab) based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline.
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Absolute risk reduction
    Point estimate
    1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 3.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.68

    Secondary: Percentage of Participants with Any Fracture Through Month 12

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    End point title
    		 Percentage of Participants with Any Fracture Through Month 12
    End point description
    All fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures. The analysis was conducted in all randomized participants.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    9.2
    6.5
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.002 [30]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [29] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [30] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with a Nonvertebral Fracture Through Month 12

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    End point title
    		 Percentage of Participants with a Nonvertebral Fracture Through Month 12
    End point description
    A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. The analysis was conducted in all randomized participants.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    4.6
    3.4
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.057 [32]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Notes
    [31] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [32] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with a Hip Fracture Through Month 12

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    End point title
    		 Percentage of Participants with a Hip Fracture Through Month 12
    End point description
    Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter. The analysis was conducted in all randomized participants.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    1.1
    0.7
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.19 [34]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 1.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Notes
    [33] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [34] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with a Major Osteoporotic Fracture Through Month 12

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    End point title
    		 Percentage of Participants with a Major Osteoporotic Fracture Through Month 12
    End point description
    Major osteoporotic fractures included clinical vertebral fractures and fractures of the hip, forearm and humerus. Fractures associated with high trauma severity or pathologic fractures were excluded. The analysis was conducted in all randomized participants.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of particiapnts
        number (not applicable)
    4.2
    3.0
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 [35]
    P-value
    		 = 0.053 [36]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Notes
    [35] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [36] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percentage of Participants with a Clinical Vertebral Fracture Through Month 12

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    End point title
    		 Percentage of Participants with a Clinical Vertebral Fracture Through Month 12
    End point description
    A clinical vertebral fracture is a new or worsening vertebral fracture assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms of back pain indicative of a fracture, regardless of trauma severity or whether it is pathologic. The analysis was conducted in all randomized participants. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    2047
    2046
    Units: percentage of participants
        number (not applicable)
    0.9
    0.5
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    4093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.14 [38]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 1.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Notes
    [37] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [38] - Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. SE represents the standard error of log (hazard ratio).

    Secondary: Percent Change from Baseline in Bone Mineral Density at the Lumbar Spine at Month 24

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    End point title
    		 Percent Change from Baseline in Bone Mineral Density at the Lumbar Spine at Month 24
    End point description
    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The analysis was conducted in all randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 24; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
    End point type
    Secondary
    End point timeframe
    Baseline and month 24
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1577
    1571
    Units: percent change
        least squares mean (standard error)
    7.2 ± 0.2
    15.3 ± 0.2
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 < 0.001 [40]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.58
         upper limit
    		 8.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Notes
    [39] - If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
    [40] - Based on ANCOVA model adjusting for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.

    Secondary: Percent Change from Baseline in Bone Mineral Density of the Total Hip at Month 24

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    End point title
    		 Percent Change from Baseline in Bone Mineral Density of the Total Hip at Month 24
    End point description
    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The analysis was conducted in all randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 24; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
    End point type
    Secondary
    End point timeframe
    Baseline and month 24
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1627
    1622
    Units: percent change
        least squares mean (standard error)
    3.5 ± 0.1
    7.2 ± 0.1
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 < 0.001 [42]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.42
         upper limit
    		 4.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [41] - If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
    [42] - Based on ANCOVA model adjusting for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.

    Secondary: Percent Change from Baseline in Bone Mineral Density of the Femoral Neck at Month 24

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    End point title
    		 Percent Change from Baseline in Bone Mineral Density of the Femoral Neck at Month 24
    End point description
    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The analysis was conducted in all randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 24; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
    End point type
    Secondary
    End point timeframe
    Baseline and month 24
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1627
    1622
    Units: percent change
        least squares mean (standard error)
    2.3 ± 0.2
    6.0 ± 0.2
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 < 0.001 [44]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.4
         upper limit
    		 4.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [43] - If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
    [44] - Based on ANCOVA model adjusting for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.

    Secondary: Percent Change from Baseline in Bone Mineral Density at the Lumbar Spine at Month 12

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    End point title
    		 Percent Change from Baseline in Bone Mineral Density at the Lumbar Spine at Month 12
    End point description
    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The analysis was conducted in all randomized participants with a baseline and ≥ 1 post-baseline evaluation at or before month 12; Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1718
    1722
    Units: percent change
        least squares mean (standard error)
    5.0 ± 0.1
    13.7 ± 0.2
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 < 0.001 [46]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    8.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.31
         upper limit
    		 9.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [45] - If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
    [46] - Based on ANCOVA model adjusting for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.

    Secondary: Percent Change from Baseline in Bone Mineral Density of the Total Hip at Month 12

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    End point title
    		 Percent Change from Baseline in Bone Mineral Density of the Total Hip at Month 12
    End point description
    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The analysis was conducted in all randomized participants with a baseline and ≥ 1 post-baseline evaluation at or before month 12; Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1781
    1781
    Units: percent change
        least squares mean (standard error)
    2.8 ± 0.1
    6.2 ± 0.1
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3562
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 < 0.001 [48]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.03
         upper limit
    		 3.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [47] - If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
    [48] - Based on ANCOVA model adjusting for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.

    Secondary: Percent Change from Baseline in Bone Mineral Density of the Femoral Neck at Month 12

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    End point title
    		 Percent Change from Baseline in Bone Mineral Density of the Femoral Neck at Month 12
    End point description
    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The analysis was conducted in all randomized participants with a baseline and ≥ 1 post-baseline evaluation at or before month 12; Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1781
    1781
    Units: percent change
        least squares mean (standard error)
    1.7 ± 0.1
    4.9 ± 0.1
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3562
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 < 0.001 [50]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.9
         upper limit
    		 3.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [49] - If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
    [50] - Based on ANCOVA model adjusting for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.

    Secondary: Percent Change from Baseline in Bone Mineral Density at the Lumbar Spine at Month 36

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    End point title
    		 Percent Change from Baseline in Bone Mineral Density at the Lumbar Spine at Month 36
    End point description
    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The analysis was conducted in all randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 36; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
    End point type
    Secondary
    End point timeframe
    Baseline and month 36
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1597
    1593
    Units: percent change
        least squares mean (standard error)
    7.8 ± 0.2
    15.2 ± 0.2
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3190
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 < 0.001 [52]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    7.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.84
         upper limit
    		 7.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Notes
    [51] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [52] - Based on ANCOVA model adjusting for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.

    Secondary: Percent Change from Baseline in Bone Mineral Density of the Total Hip at Month 36

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    End point title
    		 Percent Change from Baseline in Bone Mineral Density of the Total Hip at Month 36
    End point description
    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The analysis was conducted in all randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 36; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
    End point type
    Secondary
    End point timeframe
    Baseline and month 36
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1653
    1653
    Units: percent change
        least squares mean (standard error)
    3.5 ± 0.1
    7.2 ± 0.1
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 < 0.001 [54]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.29
         upper limit
    		 4.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [53] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [54] - Based on ANCOVA model adjusting for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.

    Secondary: Percent Change from Baseline in Bone Mineral Density of the Femoral Neck at Month 36

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    End point title
    		 Percent Change from Baseline in Bone Mineral Density of the Femoral Neck at Month 36
    End point description
    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. The analysis was conducted in all randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 36; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
    End point type
    Secondary
    End point timeframe
    Baseline and month 36
    End point values
    		 Alendronate/Alendronate Romosozumab/Alendronate
    Number of subjects analysed
    1653
    1653
    Units: percent change
        least squares mean (standard error)
    2.4 ± 0.2
    6.0 ± 0.2
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Alendronate/Alendronate v Romosozumab/Alendronate
    Number of subjects included in analysis
    3306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 < 0.001 [56]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.18
         upper limit
    		 3.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [55] - This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
    [56] - Based on ANCOVA model adjusting for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The 12-month double-blind treatment phase and overall study period which includes AEs up to the end of study for subjects who received an open-label dose and up to 12 months for subjects who did not; overall median duration of follow-up was 36 months.
    Adverse event reporting additional description
    The safety analysis set included all randomized subjects who received ≥ 1 active dose of investigational product in the 12-month double-blind alendronate-controlled study period. Two participants randomized to alendronate received romosozumab in error and are counted in the romosozumab group for safety.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    12-Month Double-blind Period: Alendronate 70 mg QW
    Reporting group description
    		 Participants received 70 mg alendronate once a week (QW) and placebo to romosozumab subcutaneously once a month for 12 months during the double-blind treatment period.

    Reporting group title
    Overall Study: Alendronate / Alendronate
    Reporting group description
    		 Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.

    Reporting group title
    Overall Study: Romosozumab / Alendronate
    Reporting group description
    		 Participants received 210 romosozumab mg subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.

    Reporting group title
    12-Month Double-blind Period: Romosozumab 210 mg QM
    Reporting group description
    		 Participants received 210 mg romosozumab subcutaneously once a month (QM) and placebo to alendronate orally once a week for the first 12 months during the double-blind treatment period.

    Serious adverse events
    		 12-Month Double-blind Period: Alendronate 70 mg QW Overall Study: Alendronate / Alendronate Overall Study: Romosozumab / Alendronate 12-Month Double-blind Period: Romosozumab 210 mg QM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    278 / 2014 (13.80%)
    638 / 2014 (31.68%)
    611 / 2040 (29.95%)
    262 / 2040 (12.84%)
         number of deaths (all causes)
    22
    103
    101
    30
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal cancer
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    2 / 2040 (0.10%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign lung neoplasm
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign renal neoplasm
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder squamous cell carcinoma stage unspecified
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer female
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 2014 (0.00%)
    4 / 2014 (0.20%)
    5 / 2040 (0.25%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Central nervous system neoplasm
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma stage IV
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choroid melanoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    3 / 2040 (0.15%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Colorectal carcinoma stage 0
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epithelioid mesothelioma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Follicular thyroid cancer
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary cancer
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hypopharyngeal cancer
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haemangioma
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal papillary mucinous neoplasm
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraocular melanoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Lung adenocarcinoma stage 0
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    3 / 2040 (0.15%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of renal pelvis
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mediastinum neoplasm
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma benign
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Metastases to adrenals
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    3 / 2040 (0.15%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to pancreas
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic bronchial carcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Myeloproliferative neoplasm
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma unspecified histology indolent stage I
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic neoplasm
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary cystadenoma lymphomatosum
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    3 / 2040 (0.15%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal neoplasm
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seborrhoeic keratosis
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestine carcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    3 / 2040 (0.15%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of pharynx
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the vulva
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric cancer
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    2 / 2040 (0.10%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 2014 (0.05%)
    4 / 2014 (0.20%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Aortic arteriosclerosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood pressure inadequately controlled
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    3 / 2040 (0.15%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    5 / 2014 (0.25%)
    9 / 2014 (0.45%)
    4 / 2040 (0.20%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    4 / 2014 (0.20%)
    8 / 2014 (0.40%)
    8 / 2040 (0.39%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 2014 (0.10%)
    5 / 2014 (0.25%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    4 / 2040 (0.20%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Hypovolaemic shock
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Labile hypertension
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 2014 (0.05%)
    5 / 2014 (0.25%)
    3 / 2040 (0.15%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 2014 (0.05%)
    3 / 2014 (0.15%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian artery occlusion
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    2 / 2040 (0.10%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgery
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Umbilical hernia repair
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse event
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    3 / 2040 (0.15%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    3 / 2040 (0.15%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 2014 (0.10%)
    21 / 2014 (1.04%)
    14 / 2040 (0.69%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 21
    0 / 14
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    1 / 21
    0 / 14
    0 / 1
    Feeling abnormal
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    3 / 2040 (0.15%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 2014 (0.10%)
    4 / 2014 (0.20%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Strangulated hernia
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    2 / 2014 (0.10%)
    4 / 2014 (0.20%)
    6 / 2040 (0.29%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
    0 / 1
    Ulcer haemorrhage
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vessel puncture site haemorrhage
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Limb prosthesis user
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of personal independence in daily activities
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colpocele
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic haematoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic prolapse
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    2 / 2040 (0.10%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    0 / 2014 (0.00%)
    3 / 2014 (0.15%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    2 / 2040 (0.10%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    5 / 2040 (0.25%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 2014 (0.10%)
    6 / 2014 (0.30%)
    5 / 2040 (0.25%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    10 / 2014 (0.50%)
    29 / 2014 (1.44%)
    24 / 2040 (1.18%)
    5 / 2040 (0.25%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 44
    0 / 33
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 2014 (0.00%)
    4 / 2014 (0.20%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    2 / 2014 (0.10%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    2 / 2040 (0.10%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paranasal cyst
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    3 / 2040 (0.15%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 2014 (0.10%)
    5 / 2014 (0.25%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    2 / 2014 (0.10%)
    3 / 2014 (0.15%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 2014 (0.10%)
    4 / 2014 (0.20%)
    2 / 2040 (0.10%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vocal cord cyst
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Confusional state
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 2014 (0.05%)
    5 / 2014 (0.25%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Ampulla of Vater stenosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary cirrhosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary fibrosis
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 2014 (0.05%)
    3 / 2014 (0.15%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 2014 (0.05%)
    3 / 2014 (0.15%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    6 / 2014 (0.30%)
    9 / 2014 (0.45%)
    7 / 2040 (0.34%)
    5 / 2040 (0.25%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 2014 (0.05%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carcinoembryonic antigen increased
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coagulation time prolonged
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heart rate decreased
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical observation normal
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Burns third degree
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Carbon monoxide poisoning
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    2 / 2040 (0.10%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 2014 (0.05%)
    7 / 2014 (0.35%)
    2 / 2040 (0.10%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    3 / 2040 (0.15%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    3 / 2040 (0.15%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    4 / 2014 (0.20%)
    11 / 2014 (0.55%)
    13 / 2040 (0.64%)
    2 / 2040 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 13
    0 / 15
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    12 / 2014 (0.60%)
    31 / 2014 (1.54%)
    15 / 2040 (0.74%)
    5 / 2040 (0.25%)
         occurrences causally related to treatment / all
    0 / 12
    1 / 31
    0 / 16
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    Femur fracture
         subjects affected / exposed
    12 / 2014 (0.60%)
    51 / 2014 (2.53%)
    42 / 2040 (2.06%)
    11 / 2040 (0.54%)
         occurrences causally related to treatment / all
    0 / 12
    2 / 51
    3 / 45
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    4 / 2014 (0.20%)
    9 / 2014 (0.45%)
    5 / 2040 (0.25%)
    3 / 2040 (0.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
    1 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    3 / 2014 (0.15%)
    5 / 2014 (0.25%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    2 / 2040 (0.10%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fractured ischium
         subjects affected / exposed
    0 / 2014 (0.00%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    0 / 2014 (0.00%)
    1 / 2014 (0.05%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    0 / 2014 (0.00%)
    0 / 2014 (0.00%)
    1 / 2040 (0.05%)
    1 / 2040 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Graft complication
         subjects affected / exposed
    1 / 2014 (0.05%)
    2 / 2014 (0.10%)
    0 / 2040 (0.00%)
    0 / 2040 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed