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Trial record 1 of 1 for:    NCT01575834
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Efficacy and Safety of Romosozumab Treatment in Postmenopausal Women With Osteoporosis (FRAME)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01575834
Recruitment Status : Completed
First Posted : April 12, 2012
Results First Posted : November 8, 2018
Last Update Posted : December 22, 2020
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Postmenopausal Osteoporosis
Interventions Drug: Romosozumab
Drug: Placebo
Drug: Denosumab
Enrollment 7180
Recruitment Details

This study was conducted at 222 centers in Europe, Central/Latin America, Asia, North America, and Australia/New Zealand.

The first participant enrolled on 15 March 2012 and the last participant enrolled on 06 December 2013.
Pre-assignment Details Participants were randomized 1:1 to receive either romosozumab 210 mg or matched placebo for the 12-month, double-blind, placebo-controlled period. Randomization was stratified by age (< 75 years, ≥ 75 years) and prevalent vertebral fracture (yes, no), as determined by site staff at randomization based on local reading of the spine X-ray.
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months. Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Period Title: Overall Study
Started 3591 3589
Received Double-blind Treatment 3582 [1] 3575
Completed Double-blind Period 3205 3185
Completed 24-month Study Period 3032 2994
Completed 2892 [2] 2851 [2]
Not Completed 699 738
Reason Not Completed
Withdrawal by Subject             352             390
Death             81             74
Other             70             70
Adverse Event             63             61
Lost to Follow-up             55             68
Noncompliance             52             27
Administrative decision             15             33
Ineligibility Determined             5             8
Protocol Deviation             4             3
Requirement for Alternative Therapy             2             4
[1]
Six participants received a dose of romosozumab in error during the double-blind period.
[2]
Completed 36-month study period
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab Total
Hide Arm/Group Description Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months. Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months. Total of all reporting groups
Overall Number of Baseline Participants 3591 3589 7180
Hide Baseline Analysis Population Description
The full analysis set consisted of all randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3591 participants 3589 participants 7180 participants
70.8  (6.9) 70.9  (7.0) 70.9  (7.0)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3591 participants 3589 participants 7180 participants
< 65 years
757
  21.1%
768
  21.4%
1525
  21.2%
≥ 65 years
2834
  78.9%
2821
  78.6%
5655
  78.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3591 participants 3589 participants 7180 participants
Female
3591
 100.0%
3589
 100.0%
7180
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3591 participants 3589 participants 7180 participants
Hispanic or Latino
1416
  39.4%
1427
  39.8%
2843
  39.6%
Not Hispanic or Latino
2175
  60.6%
2162
  60.2%
4337
  60.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3591 participants 3589 participants 7180 participants
White
2052
  57.1%
2063
  57.5%
4115
  57.3%
Asian
441
  12.3%
425
  11.8%
866
  12.1%
Black or African American
74
   2.1%
77
   2.1%
151
   2.1%
American Indian/Alaska Native
63
   1.8%
64
   1.8%
127
   1.8%
Native Hawaiian/Other Pacific Islander
1
   0.0%
0
   0.0%
1
   0.0%
Multiple
59
   1.6%
60
   1.7%
119
   1.7%
Other
901
  25.1%
900
  25.1%
1801
  25.1%
Prevalent Vertebral Fracture Strata per Randomization   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3591 participants 3589 participants 7180 participants
Yes
205
   5.7%
204
   5.7%
409
   5.7%
No
3386
  94.3%
3385
  94.3%
6771
  94.3%
[1]
Measure Description: Strata per randomization for prevalent fracture were based on local reading of baseline spine radiographs.
Age Strata per Randomization  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3591 participants 3589 participants 7180 participants
< 75 years
2471
  68.8%
2470
  68.8%
4941
  68.8%
≥ 75 years
1120
  31.2%
1119
  31.2%
2239
  31.2%
1.Primary Outcome
Title Percentage of Participants With New Vertebral Fracture Through Month 12
Hide 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.

The Genant semiquantitative scoring method was 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.
Time Frame 12 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 12 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3322 3321
Measure Type: Number
Unit of Measure: percentage of participants
1.8 0.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Regression, Logistic
Comments Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.27
Confidence Interval (2-Sided) 95%
0.15 to 0.47
Estimation Comments Values < 1 for odds ratio favor romosozumab.
2.Primary Outcome
Title Percentage of Participants With New Vertebral Fracture Through Month 24
Hide 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.

The Genant semiquantitative scoring method was 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.
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 24 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 3327 3325
Measure Type: Number
Unit of Measure: percentage of participants
2.5 0.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Regression, Logistic
Comments Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.24
Confidence Interval (2-Sided) 95%
0.15 to 0.39
Estimation Comments Values < 1 for odds ratio favor romosozumab.
3.Secondary Outcome
Title Percentage of Participants With a Clinical Fracture Through Month 12
Hide 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.
Time Frame 12 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set; Last observation carried forward imputation (LOCF) was used.
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3591 3589
Measure Type: Number
Unit of Measure: percentage of participants
2.5 1.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.008
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Cox proportional hazards
Comments Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.64
Confidence Interval (2-Sided) 95%
0.46 to 0.89
Estimation Comments Hazard ratio < 1 favors romosozumab.
4.Secondary Outcome
Title Percentage of Participants With a Nonvertebral Fracture Through Month 12
Hide 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.
Time Frame 12 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3591 3589
Measure Type: Number
Unit of Measure: percentage of participants
2.1 1.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.096
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Cox proportional hazards
Comments Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.75
Confidence Interval (2-Sided) 95%
0.53 to 1.05
Estimation Comments Hazard ratio < 1 favors romosozumab.
5.Secondary Outcome
Title Percentage of Participants With a Nonvertebral Fracture Through Month 24
Hide 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 as 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.
Time Frame 24 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 3591 3589
Measure Type: Number
Unit of Measure: percentage of participants
3.6 2.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.057
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Cox proportional hazards
Comments Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.75
Confidence Interval (2-Sided) 95%
0.57 to 0.97
Estimation Comments Hazard ratio < 1 favors romosozumab.
6.Secondary Outcome
Title Percentage of Participants With a Clinical Fracture Through Month 24
Hide 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.
Time Frame 24 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set; LOCF imputation was used
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 3591 3589
Measure Type: Number
Unit of Measure: percentage of participants
4.1 2.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.096
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Cox proportional hazards
Comments Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
0.52 to 0.87
Estimation Comments Hazard ratio < 1 favors romosozumab.
7.Secondary Outcome
Title Percentage of Participants With a Major Nonvertebral Fracture Through Month 12
Hide 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.
Time Frame 12 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3591 3589
Measure Type: Number
Unit of Measure: percentage of participants
1.5 1.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.096
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Cox proportional hazards
Comments Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
0.44 to 1.02
Estimation Comments Hazard ratio < 1 favors romosozumab.
8.Secondary Outcome
Title Percentage of Participants With a Major Nonvertebral Fracture Through Month 24
Hide 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.
Time Frame 24 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 3591 3589
Measure Type: Number
Unit of Measure: percentage of participants
2.8 1.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.096
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Cox proportional hazards
Comments Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
0.49 to 0.91
Estimation Comments Hazard ratio < 1 favors romosozumab
9.Secondary Outcome
Title Percentage of Participants With a New or Worsening Vertebral Fracture Through Month 12
Hide 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.
Time Frame 12 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 24 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. LOCF imputation was used
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3322 3321
Measure Type: Number
Unit of Measure: percentage of participants
1.8 0.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.096
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Regression, Logistic
Comments Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.28
Confidence Interval (2-Sided) 95%
0.17 to 0.49
Estimation Comments Values < 1 for odds ratio favor romosozumab.
10.Secondary Outcome
Title Percentage of Participants With a New or Worsening Vertebral Fracture Through Month 24
Hide 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.
Time Frame 24 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 24 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. LOCF imputation was used.
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 3327 3325
Measure Type: Number
Unit of Measure: percentage of participants
2.5 0.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.096
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Regression, Logistic
Comments Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.26
Confidence Interval (2-Sided) 95%
0.16 to 0.41
Estimation Comments Values < 1 for odds ratio favor romosozumab.
11.Secondary Outcome
Title Percentage of Participants With a Hip Fracture Through Month 12
Hide Description Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.
Time Frame 12 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3591 3589
Measure Type: Number
Unit of Measure: percentage of participants
0.4 0.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.18
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Cox proportional hazards
Comments Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.54
Confidence Interval (2-Sided) 95%
0.22 to 1.35
Estimation Comments Hazard ratio < 1 favors romosozumab.
12.Secondary Outcome
Title Percentage of Participants With a Hip Fracture Through Month 24
Hide Description Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.
Time Frame 24 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 3591 3589
Measure Type: Number
Unit of Measure: percentage of participants
0.6 0.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.12
Comments A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
Method Cox proportional hazards
Comments Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.50
Confidence Interval (2-Sided) 95%
0.24 to 1.04
Estimation Comments Hazard ratio < 1 favors romosozumab.
13.Secondary Outcome
Title Percentage of Participants With a Major Osteoporotic Fracture Through Month 12
Hide 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.
Time Frame 12 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3591 3589
Measure Type: Number
Unit of Measure: percentage of participants
1.8 1.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.012
Comments [Not Specified]
Method Cox proportional hazards
Comments Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
0.40 to 0.90
Estimation Comments Hazard ratio < 1 favors romosozumab.
14.Secondary Outcome
Title Percentage of Participants With a Major Osteoporotic Fracture Through Month 24
Hide 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.
Time Frame 24 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 3591 3589
Measure Type: Number
Unit of Measure: percentage of participants
3.1 1.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method Cox proportional hazards
Comments Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.46 to 0.84
Estimation Comments Hazard ratio < 1 favors romosozumab.
15.Secondary Outcome
Title Percentage of Participants With Multiple New or Worsening Vertebral Fractures Through Month 12
Hide 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.
Time Frame 12 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 24 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. LOCF imputation was used.
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3322 3321
Measure Type: Number
Unit of Measure: percentage of participants
0.3 0.03
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.011
Comments [Not Specified]
Method Regression, Logistic
Comments Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.11
Confidence Interval (2-Sided) 95%
0.01 to 0.87
Estimation Comments Values < 1 for odds ratio favor romosozumab.
16.Secondary Outcome
Title Percentage of Participants With Multiple New or Worsening Vertebral Fractures Through Month 24
Hide 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.
Time Frame 24 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 24 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. LOCF imputation was used.
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 3327 3325
Measure Type: Number
Unit of Measure: percentage of participants
0.5 0.03
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.06
Confidence Interval (2-Sided) 95%
0.01 to 0.44
Estimation Comments Values < 1 for odds ratio favor romosozumab.
17.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 12
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3148 3151
Least Squares Mean (Standard Error)
Unit of Measure: percent change
0.4  (0.1) 13.1  (0.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments The treatment comparison of BMD at the lumbar spine was analyzed using an analysis of covariance (ANCOVA) model which included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 12.7
Confidence Interval (2-Sided) 95%
12.4 to 12.9
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.1
Estimation Comments [Not Specified]
18.Secondary Outcome
Title Percent Change From Baseline In Bone Mineral Density at the Lumbar Spine at Month 24
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 2877 2861
Least Squares Mean (Standard Error)
Unit of Measure: percent change
5.5  (0.1) 16.6  (0.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments The treatment comparison of BMD at the lumbar spine was analyzed using an analysis of covariance (ANCOVA) model which included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 11.1
Confidence Interval (2-Sided) 95%
10.8 to 11.4
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.1
Estimation Comments [Not Specified]
19.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 12
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3210 3197
Least Squares Mean (Standard Error)
Unit of Measure: percent change
0.3  (0.1) 6.0  (0.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments The treatment comparison of BMD at the total hip was analyzed using an ANCOVA model which included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 5.8
Confidence Interval (2-Sided) 95%
5.6 to 6.0
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.1
Estimation Comments [Not Specified]
20.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 24
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 2918 2903
Least Squares Mean (Standard Error)
Unit of Measure: percent change
3.2  (0.1) 8.5  (0.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments The treatment comparison of BMD at the total hip was analyzed using an ANCOVA model which included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 5.3
Confidence Interval (2-Sided) 95%
5.1 to 5.5
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.1
Estimation Comments [Not Specified]
21.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at Month 12
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.
Arm/Group Title Placebo Romosozumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Overall Number of Participants Analyzed 3210 3197
Least Squares Mean (Standard Error)
Unit of Measure: percent change
0.3  (0.1) 5.5  (0.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Romosozumab
Comments The treatment comparison of BMD at the femoral neck was analyzed using an ANCOVA model which included included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 5.2
Confidence Interval (2-Sided) 95%
4.9 to 5.4
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.1
Estimation Comments [Not Specified]
22.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at Month 24
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.
Arm/Group Title Placebo/Denosumab Romosozumab/Denosumab
Hide Arm/Group Description:
Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Overall Number of Participants Analyzed 2918 2903
Least Squares Mean (Standard Error)
Unit of Measure: percent change
2.3  (0.1) 7.3  (0.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Denosumab, Romosozumab/Denosumab
Comments The treatment comparison of BMD at the femoral neck was analyzed using an ANCOVA model which included included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 4.9
Confidence Interval (2-Sided) 95%
4.7 to 5.2
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.1
Estimation Comments [Not Specified]
Time Frame Double-blind treatment period: 12 months; Overall study: 36 months
Adverse Event Reporting Description

Six participants randomized to placebo received a dose of romosozumab in error during the double-blind period. Therefore, these 6 participants were included in the romosozumab group (ie, as treated) for safety analyses.

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
 
Arm/Group Title 12-Month Double-blind Period: Placebo 12-Month Double-blind Period: Romosozumab 36-Month Study Period: Placebo/Denosumab 36-Month Study Period: Romosozumab/Denosumab
Hide Arm/Group Description Participants received placebo subcutaneous injections once a month for 12 months Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months. Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months. Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
All-Cause Mortality
12-Month Double-blind Period: Placebo 12-Month Double-blind Period: Romosozumab 36-Month Study Period: Placebo/Denosumab 36-Month Study Period: Romosozumab/Denosumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
12-Month Double-blind Period: Placebo 12-Month Double-blind Period: Romosozumab 36-Month Study Period: Placebo/Denosumab 36-Month Study Period: Romosozumab/Denosumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   314/3576 (8.78%)   344/3581 (9.61%)   733/3576 (20.50%)   728/3581 (20.33%) 
Blood and lymphatic system disorders         
Agranulocytosis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Anaemia † 1  4/3576 (0.11%)  2/3581 (0.06%)  9/3576 (0.25%)  4/3581 (0.11%) 
Anaemia of chronic disease † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Aplastic anaemia † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Autoimmune haemolytic anaemia † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Coagulopathy † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hypocoagulable state † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Iron deficiency anaemia † 1  1/3576 (0.03%)  1/3581 (0.03%)  2/3576 (0.06%)  4/3581 (0.11%) 
Lymphadenitis † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Lymphadenopathy † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Neutropenia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pancytopenia † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Pernicious anaemia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Thrombocytopenia † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Cardiac disorders         
Acute coronary syndrome † 1  3/3576 (0.08%)  0/3581 (0.00%)  5/3576 (0.14%)  2/3581 (0.06%) 
Acute myocardial infarction † 1  4/3576 (0.11%)  6/3581 (0.17%)  10/3576 (0.28%)  16/3581 (0.45%) 
Adams-Stokes syndrome † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Angina pectoris † 1  3/3576 (0.08%)  3/3581 (0.08%)  5/3576 (0.14%)  7/3581 (0.20%) 
Angina unstable † 1  3/3576 (0.08%)  6/3581 (0.17%)  9/3576 (0.25%)  10/3581 (0.28%) 
Aortic valve disease mixed † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Aortic valve stenosis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Arrhythmia † 1  1/3576 (0.03%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Arrhythmia supraventricular † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Arteriosclerosis coronary artery † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Atrial fibrillation † 1  4/3576 (0.11%)  6/3581 (0.17%)  18/3576 (0.50%)  17/3581 (0.47%) 
Atrioventricular block † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Atrioventricular block complete † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Bradycardia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  2/3581 (0.06%) 
Cardiac arrest † 1  1/3576 (0.03%)  1/3581 (0.03%)  3/3576 (0.08%)  2/3581 (0.06%) 
Cardiac failure † 1  1/3576 (0.03%)  5/3581 (0.14%)  7/3576 (0.20%)  10/3581 (0.28%) 
Cardiac failure acute † 1  1/3576 (0.03%)  1/3581 (0.03%)  4/3576 (0.11%)  2/3581 (0.06%) 
Cardiac failure chronic † 1  1/3576 (0.03%)  0/3581 (0.00%)  5/3576 (0.14%)  3/3581 (0.08%) 
Cardiac failure congestive † 1  4/3576 (0.11%)  7/3581 (0.20%)  8/3576 (0.22%)  10/3581 (0.28%) 
Cardio-respiratory arrest † 1  0/3576 (0.00%)  2/3581 (0.06%)  5/3576 (0.14%)  4/3581 (0.11%) 
Cardiogenic shock † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Cardiopulmonary failure † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Congestive cardiomyopathy † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Cor pulmonale † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  2/3581 (0.06%) 
Coronary artery disease † 1  3/3576 (0.08%)  4/3581 (0.11%)  7/3576 (0.20%)  7/3581 (0.20%) 
Coronary artery insufficiency † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Coronary artery stenosis † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  2/3581 (0.06%) 
Heart valve incompetence † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hypertensive heart disease † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Ischaemic cardiomyopathy † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Low cardiac output syndrome † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Mitral valve prolapse † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Mitral valve stenosis † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Myocardial infarction † 1  2/3576 (0.06%)  2/3581 (0.06%)  9/3576 (0.25%)  8/3581 (0.22%) 
Myocardial ischaemia † 1  4/3576 (0.11%)  3/3581 (0.08%)  7/3576 (0.20%)  3/3581 (0.08%) 
Palpitations † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Paroxysmal atrioventricular block † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Prinzmetal angina † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Sinus bradycardia † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Sinus node dysfunction † 1  2/3576 (0.06%)  1/3581 (0.03%)  2/3576 (0.06%)  4/3581 (0.11%) 
Stress cardiomyopathy † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Supraventricular tachycardia † 1  3/3576 (0.08%)  0/3581 (0.00%)  5/3576 (0.14%)  1/3581 (0.03%) 
Ventricular tachycardia † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Congenital, familial and genetic disorders         
Dermoid cyst † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Ear and labyrinth disorders         
Acute vestibular syndrome † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Deafness unilateral † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Hypoacusis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Meniere's disease † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Vertigo † 1  3/3576 (0.08%)  2/3581 (0.06%)  5/3576 (0.14%)  2/3581 (0.06%) 
Vertigo positional † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Vestibular ataxia † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Endocrine disorders         
Goitre † 1  1/3576 (0.03%)  2/3581 (0.06%)  3/3576 (0.08%)  5/3581 (0.14%) 
Hyperthyroidism † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Primary hyperaldosteronism † 1  1/3576 (0.03%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Eye disorders         
Age-related macular degeneration † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Angle closure glaucoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Blindness unilateral † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Cataract † 1  5/3576 (0.14%)  4/3581 (0.11%)  14/3576 (0.39%)  13/3581 (0.36%) 
Cystoid macular oedema † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Glaucoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Lens disorder † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Posterior capsule rupture † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Retinal detachment † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Retinal disorder † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Uveitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Gastrointestinal disorders         
Abdominal adhesions † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Abdominal hernia † 1  0/3576 (0.00%)  2/3581 (0.06%)  0/3576 (0.00%)  3/3581 (0.08%) 
Abdominal incarcerated hernia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Abdominal pain † 1  3/3576 (0.08%)  4/3581 (0.11%)  9/3576 (0.25%)  10/3581 (0.28%) 
Abdominal pain upper † 1  1/3576 (0.03%)  0/3581 (0.00%)  3/3576 (0.08%)  1/3581 (0.03%) 
Acute abdomen † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Anal fissure † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Anal prolapse † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Chronic gastritis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  2/3581 (0.06%) 
Coeliac disease † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Colitis † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  2/3581 (0.06%) 
Colitis ischaemic † 1  1/3576 (0.03%)  1/3581 (0.03%)  2/3576 (0.06%)  2/3581 (0.06%) 
Constipation † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Diarrhoea † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Diverticular perforation † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Diverticulum † 1  0/3576 (0.00%)  4/3581 (0.11%)  2/3576 (0.06%)  5/3581 (0.14%) 
Diverticulum intestinal † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  2/3581 (0.06%) 
Duodenal ulcer haemorrhage † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Dyspepsia † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  2/3581 (0.06%) 
Dysphagia † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Enteritis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Faecaloma † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Femoral hernia † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Fistula of small intestine † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Functional gastrointestinal disorder † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Gastric haemorrhage † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Gastric polyps † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Gastric ulcer † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Gastric ulcer haemorrhage † 1  1/3576 (0.03%)  0/3581 (0.00%)  3/3576 (0.08%)  0/3581 (0.00%) 
Gastric ulcer perforation † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Gastritis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  2/3581 (0.06%) 
Gastrointestinal angiodysplasia † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Gastrointestinal haemorrhage † 1  1/3576 (0.03%)  1/3581 (0.03%)  6/3576 (0.17%)  2/3581 (0.06%) 
Gastrointestinal hypomotility † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Gastrointestinal necrosis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Gastrooesophageal reflux disease † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  3/3581 (0.08%) 
Haemorrhoidal haemorrhage † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Haemorrhoids † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Hernial eventration † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hiatus hernia † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  2/3581 (0.06%) 
Ileus † 1  1/3576 (0.03%)  1/3581 (0.03%)  2/3576 (0.06%)  2/3581 (0.06%) 
Ileus paralytic † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Incarcerated inguinal hernia † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Incarcerated umbilical hernia † 1  1/3576 (0.03%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Inguinal hernia † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Intestinal ischaemia † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Intestinal obstruction † 1  1/3576 (0.03%)  2/3581 (0.06%)  3/3576 (0.08%)  3/3581 (0.08%) 
Intestinal perforation † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Irritable bowel syndrome † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Large intestinal ulcer † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Large intestine perforation † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Large intestine polyp † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Lower gastrointestinal haemorrhage † 1  1/3576 (0.03%)  1/3581 (0.03%)  1/3576 (0.03%)  3/3581 (0.08%) 
Mallory-Weiss syndrome † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Mechanical ileus † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Melaena † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Mesenteric artery thrombosis † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Nausea † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Oesophageal varices haemorrhage † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Pancreatic cyst † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Pancreatic cyst rupture † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Pancreatic fistula † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Pancreatitis † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  2/3581 (0.06%) 
Pancreatitis acute † 1  1/3576 (0.03%)  1/3581 (0.03%)  1/3576 (0.03%)  6/3581 (0.17%) 
Pancreatitis chronic † 1  2/3576 (0.06%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Peritoneal adhesions † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Rectal prolapse † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Reflux gastritis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  2/3581 (0.06%) 
Retroperitoneal haematoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Small intestinal obstruction † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  2/3581 (0.06%) 
Small intestinal perforation † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Toothache † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Umbilical hernia † 1  1/3576 (0.03%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Upper gastrointestinal haemorrhage † 1  1/3576 (0.03%)  1/3581 (0.03%)  3/3576 (0.08%)  2/3581 (0.06%) 
Vomiting † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  3/3581 (0.08%) 
General disorders         
Asthenia † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Chest pain † 1  1/3576 (0.03%)  3/3581 (0.08%)  3/3576 (0.08%)  4/3581 (0.11%) 
Complication associated with device † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Death † 1  5/3576 (0.14%)  5/3581 (0.14%)  9/3576 (0.25%)  13/3581 (0.36%) 
General physical health deterioration † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Malaise † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Medical device discomfort † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Mucosal dryness † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Multiple organ dysfunction syndrome † 1  1/3576 (0.03%)  1/3581 (0.03%)  3/3576 (0.08%)  2/3581 (0.06%) 
Non-cardiac chest pain † 1  0/3576 (0.00%)  4/3581 (0.11%)  3/3576 (0.08%)  10/3581 (0.28%) 
Oedema peripheral † 1  1/3576 (0.03%)  0/3581 (0.00%)  3/3576 (0.08%)  0/3581 (0.00%) 
Pyrexia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Sudden death † 1  1/3576 (0.03%)  0/3581 (0.00%)  4/3576 (0.11%)  0/3581 (0.00%) 
Hepatobiliary disorders         
Autoimmune hepatitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Bile duct stone † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Biliary colic † 1  0/3576 (0.00%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Biliary dilatation † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Cholangitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Cholangitis sclerosing † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Cholecystitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  3/3576 (0.08%)  2/3581 (0.06%) 
Cholecystitis acute † 1  1/3576 (0.03%)  3/3581 (0.08%)  6/3576 (0.17%)  5/3581 (0.14%) 
Cholecystitis chronic † 1  0/3576 (0.00%)  2/3581 (0.06%)  0/3576 (0.00%)  2/3581 (0.06%) 
Cholelithiasis † 1  8/3576 (0.22%)  5/3581 (0.14%)  11/3576 (0.31%)  12/3581 (0.34%) 
Cholelithiasis obstructive † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Cholestasis † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Drug-induced liver injury † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Hepatic cyst † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hepatic failure † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hepatic steatosis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Hepatocellular injury † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Ischaemic hepatitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Jaundice † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Jaundice cholestatic † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Liver disorder † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Liver injury † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Portal hypertension † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Portal vein thrombosis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Sphincter of Oddi dysfunction † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Immune system disorders         
Anaphylactic shock † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Drug hypersensitivity † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hypersensitivity † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Infections and infestations         
Abdominal sepsis † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Abscess † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Abscess limb † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  2/3581 (0.06%) 
Amoebiasis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Amoebic colitis † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Amoebic dysentery † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Appendicitis † 1  2/3576 (0.06%)  1/3581 (0.03%)  7/3576 (0.20%)  4/3581 (0.11%) 
Appendicitis perforated † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  2/3581 (0.06%) 
Arthritis bacterial † 1  1/3576 (0.03%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Bacterial tracheitis † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Bronchitis † 1  1/3576 (0.03%)  4/3581 (0.11%)  3/3576 (0.08%)  9/3581 (0.25%) 
Bronchitis bacterial † 1  1/3576 (0.03%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Bronchitis viral † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Cellulitis † 1  2/3576 (0.06%)  5/3581 (0.14%)  11/3576 (0.31%)  11/3581 (0.31%) 
Chikungunya virus infection † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Chlamydial infection † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Chronic sinusitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Clostridium colitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Clostridium difficile colitis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  3/3581 (0.08%) 
Cystitis † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Dengue fever † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Dermatitis infected † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Diverticulitis † 1  3/3576 (0.08%)  1/3581 (0.03%)  6/3576 (0.17%)  3/3581 (0.08%) 
Empyema † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  2/3581 (0.06%) 
Encephalitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Enterobacter bacteraemia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Erysipelas † 1  1/3576 (0.03%)  2/3581 (0.06%)  3/3576 (0.08%)  3/3581 (0.08%) 
Escherichia sepsis † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Escherichia urinary tract infection † 1  1/3576 (0.03%)  0/3581 (0.00%)  3/3576 (0.08%)  0/3581 (0.00%) 
Eye infection † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Gangrene † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Gastroenteritis † 1  0/3576 (0.00%)  1/3581 (0.03%)  3/3576 (0.08%)  6/3581 (0.17%) 
Gastroenteritis bacterial † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Gastroenteritis viral † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Hepatitis B † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hepatitis C † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Hepatitis viral † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Herpes zoster † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Infected dermal cyst † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Infected skin ulcer † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  2/3581 (0.06%) 
Infective exacerbation of bronchiectasis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Infective exacerbation of chronic obstructive airways disease † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Influenza † 1  2/3576 (0.06%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Intestinal gangrene † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Labyrinthitis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Liver abscess † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Lower respiratory tract infection † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  2/3581 (0.06%) 
Lyme disease † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Lymphangitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  2/3581 (0.06%) 
Medical device site joint infection † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Meningitis pneumococcal † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Mycobacterium avium complex infection † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Osteomyelitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Osteomyelitis chronic † 1  2/3576 (0.06%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Otitis media acute † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Perichondritis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Perineal abscess † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Perirectal abscess † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Peritonitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Peritonitis bacterial † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Pharyngitis bacterial † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Phlebitis infective † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pneumococcal sepsis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pneumonia † 1  10/3576 (0.28%)  19/3581 (0.53%)  37/3576 (1.03%)  44/3581 (1.23%) 
Pneumonia bacterial † 1  2/3576 (0.06%)  2/3581 (0.06%)  4/3576 (0.11%)  2/3581 (0.06%) 
Pneumonia cryptococcal † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pneumonia haemophilus † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Pneumonia mycoplasmal † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Postoperative wound infection † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  2/3581 (0.06%) 
Pulmonary sepsis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Pulmonary tuberculosis † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pyelocystitis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pyelonephritis † 1  0/3576 (0.00%)  0/3581 (0.00%)  3/3576 (0.08%)  1/3581 (0.03%) 
Pyelonephritis acute † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pyometra † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Pyonephrosis † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Salmonellosis † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  2/3581 (0.06%) 
Sepsis † 1  1/3576 (0.03%)  4/3581 (0.11%)  3/3576 (0.08%)  7/3581 (0.20%) 
Septic shock † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  4/3581 (0.11%) 
Sinusitis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  2/3581 (0.06%) 
Skin infection † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Staphylococcal infection † 1  0/3576 (0.00%)  2/3581 (0.06%)  0/3576 (0.00%)  2/3581 (0.06%) 
Streptococcal sepsis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Tick-borne viral encephalitis † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Upper respiratory tract infection † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Ureteritis † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Urinary tract infection † 1  7/3576 (0.20%)  4/3581 (0.11%)  14/3576 (0.39%)  17/3581 (0.47%) 
Urinary tract infection bacterial † 1  3/3576 (0.08%)  3/3581 (0.08%)  4/3576 (0.11%)  4/3581 (0.11%) 
Urosepsis † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  2/3581 (0.06%) 
Vaginitis bacterial † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Vestibular neuronitis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Wound abscess † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Injury, poisoning and procedural complications         
Abdominal wound dehiscence † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Accidental overdose † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Acetabulum fracture † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Animal bite † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Brain contusion † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Cataract operation complication † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Concussion † 1  1/3576 (0.03%)  0/3581 (0.00%)  3/3576 (0.08%)  1/3581 (0.03%) 
Contusion † 1  2/3576 (0.06%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Craniocerebral injury † 1  3/3576 (0.08%)  1/3581 (0.03%)  4/3576 (0.11%)  2/3581 (0.06%) 
Eye injury † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Eyelid injury † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Face injury † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Facial bones fracture † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Fall † 1  1/3576 (0.03%)  0/3581 (0.00%)  6/3576 (0.17%)  7/3581 (0.20%) 
Femoral neck fracture † 1  8/3576 (0.22%)  3/3581 (0.08%)  14/3576 (0.39%)  11/3581 (0.31%) 
Femur fracture † 1  7/3576 (0.20%)  4/3581 (0.11%)  19/3576 (0.53%)  9/3581 (0.25%) 
Fibula fracture † 1  4/3576 (0.11%)  4/3581 (0.11%)  8/3576 (0.22%)  7/3581 (0.20%) 
Foot fracture † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Foreign body † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Fractured sacrum † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Gastrointestinal stoma complication † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Hand fracture † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Head injury † 1  1/3576 (0.03%)  2/3581 (0.06%)  3/3576 (0.08%)  6/3581 (0.17%) 
Humerus fracture † 1  0/3576 (0.00%)  1/3581 (0.03%)  8/3576 (0.22%)  8/3581 (0.22%) 
Incisional hernia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Injury † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Internal injury † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Joint dislocation † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Joint injury † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Ligament sprain † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Limb injury † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Lumbar vertebral fracture † 1  1/3576 (0.03%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Meniscus injury † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Multiple injuries † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Muscle rupture † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Muscle strain † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Overdose † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Patella fracture † 1  1/3576 (0.03%)  0/3581 (0.00%)  4/3576 (0.11%)  2/3581 (0.06%) 
Pneumothorax traumatic † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Post concussion syndrome † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Post procedural complication † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Post procedural haemorrhage † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Postoperative adhesion † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Postoperative delirium † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Procedural complication † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Procedural hypotension † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Procedural pain † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pubis fracture † 1  0/3576 (0.00%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Radial head dislocation † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Radius fracture † 1  5/3576 (0.14%)  3/3581 (0.08%)  17/3576 (0.48%)  14/3581 (0.39%) 
Rib fracture † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  3/3581 (0.08%) 
Road traffic accident † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Spinal fracture † 1  0/3576 (0.00%)  1/3581 (0.03%)  3/3576 (0.08%)  2/3581 (0.06%) 
Sternal fracture † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Stoma site ischaemia † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Subarachnoid haemorrhage † 1  0/3576 (0.00%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Subdural haematoma † 1  1/3576 (0.03%)  1/3581 (0.03%)  2/3576 (0.06%)  2/3581 (0.06%) 
Tendon rupture † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Thoracic vertebral fracture † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Tibia fracture † 1  4/3576 (0.11%)  4/3581 (0.11%)  7/3576 (0.20%)  7/3581 (0.20%) 
Toxicity to various agents † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Ulna fracture † 1  4/3576 (0.11%)  2/3581 (0.06%)  12/3576 (0.34%)  8/3581 (0.22%) 
Uterine dehiscence † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Wound † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Wound complication † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Wound evisceration † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Wound haemorrhage † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Wound necrosis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Investigations         
Blood lactic acid increased † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Blood pressure decreased † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Blood pressure increased † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Body mass index increased † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Fibrin D dimer increased † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Gastric pH decreased † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
General physical condition abnormal † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Haemoglobin decreased † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Hepatic enzyme increased † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Influenza B virus test positive † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Liver function test increased † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Transaminases increased † 1  1/3576 (0.03%)  1/3581 (0.03%)  2/3576 (0.06%)  2/3581 (0.06%) 
Metabolism and nutrition disorders         
Decreased appetite † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Dehydration † 1  0/3576 (0.00%)  2/3581 (0.06%)  1/3576 (0.03%)  7/3581 (0.20%) 
Diabetes mellitus † 1  0/3576 (0.00%)  1/3581 (0.03%)  3/3576 (0.08%)  4/3581 (0.11%) 
Diabetes mellitus inadequate control † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  2/3581 (0.06%) 
Diabetic ketoacidosis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  3/3581 (0.08%) 
Diabetic metabolic decompensation † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  2/3581 (0.06%) 
Electrolyte imbalance † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Folate deficiency † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Hypercalcaemia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Hyperglycaemia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Hyperkalaemia † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Hypernatraemia † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hypocalcaemia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Hypochloraemia † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Hypoglycaemia † 1  2/3576 (0.06%)  0/3581 (0.00%)  2/3576 (0.06%)  2/3581 (0.06%) 
Hypokalaemia † 1  1/3576 (0.03%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Hyponatraemia † 1  0/3576 (0.00%)  3/3581 (0.08%)  5/3576 (0.14%)  4/3581 (0.11%) 
Hyponatraemic syndrome † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hypoosmolar state † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Malnutrition † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Mineral metabolism disorder † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Type 2 diabetes mellitus † 1  1/3576 (0.03%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Vitamin B12 deficiency † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Musculoskeletal and connective tissue disorders         
Arthralgia † 1  1/3576 (0.03%)  0/3581 (0.00%)  4/3576 (0.11%)  0/3581 (0.00%) 
Arthritis † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  2/3581 (0.06%) 
Arthropathy † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Back pain † 1  1/3576 (0.03%)  2/3581 (0.06%)  5/3576 (0.14%)  5/3581 (0.14%) 
Bursitis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Chondrocalcinosis pyrophosphate † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Coccydynia † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Costochondritis † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  2/3581 (0.06%) 
Foot deformity † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Fracture pain † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Haemarthrosis † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Intervertebral disc compression † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Intervertebral disc degeneration † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Intervertebral disc disorder † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Intervertebral disc protrusion † 1  2/3576 (0.06%)  0/3581 (0.00%)  4/3576 (0.11%)  4/3581 (0.11%) 
Lumbar spinal stenosis † 1  2/3576 (0.06%)  0/3581 (0.00%)  5/3576 (0.14%)  3/3581 (0.08%) 
Meniscal degeneration † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Muscle haemorrhage † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Myalgia † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Osteitis deformans † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Osteoarthritis † 1  15/3576 (0.42%)  6/3581 (0.17%)  27/3576 (0.76%)  21/3581 (0.59%) 
Osteonecrosis † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Osteonecrosis of jaw † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pain in extremity † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  2/3581 (0.06%) 
Pain in jaw † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Polymyalgia rheumatica † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Psoriatic arthropathy † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Rotator cuff syndrome † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Scoliosis † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Spinal column stenosis † 1  3/3576 (0.08%)  1/3581 (0.03%)  5/3576 (0.14%)  4/3581 (0.11%) 
Spinal osteoarthritis † 1  2/3576 (0.06%)  0/3581 (0.00%)  10/3576 (0.28%)  1/3581 (0.03%) 
Spinal pain † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Spondylolisthesis † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Synovial cyst † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Systemic lupus erythematosus † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Trigger finger † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Acral lentiginous melanoma † 1  0/3576 (0.00%)  2/3581 (0.06%)  0/3576 (0.00%)  2/3581 (0.06%) 
Acute myeloid leukaemia † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  2/3581 (0.06%) 
Adenocarcinoma gastric † 1  2/3576 (0.06%)  1/3581 (0.03%)  8/3576 (0.22%)  2/3581 (0.06%) 
Adenocarcinoma of colon † 1  2/3576 (0.06%)  0/3581 (0.00%)  4/3576 (0.11%)  2/3581 (0.06%) 
Adenocarcinoma pancreas † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Adrenal adenoma † 1  2/3576 (0.06%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Adrenal neoplasm † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Anal cancer † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Angiocentric lymphoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Basal cell carcinoma † 1  5/3576 (0.14%)  2/3581 (0.06%)  6/3576 (0.17%)  7/3581 (0.20%) 
Basosquamous carcinoma † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Benign breast neoplasm † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Benign gastric neoplasm † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Benign neoplasm of adrenal gland † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Benign neoplasm of bladder † 1  0/3576 (0.00%)  1/3581 (0.03%)  1/3576 (0.03%)  1/3581 (0.03%) 
Benign neoplasm of spinal cord † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Benign ovarian tumour † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Benign pleural neoplasm † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Benign salivary gland neoplasm † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Benign soft tissue neoplasm † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Bladder cancer † 1  1/3576 (0.03%)  0/3581 (0.00%)  4/3576 (0.11%)  0/3581 (0.00%) 
Bladder transitional cell carcinoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  0/3581 (0.00%) 
Bowen's disease † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Brain neoplasm malignant † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Breast cancer † 1  3/3576 (0.08%)  1/3581 (0.03%)  11/3576 (0.31%)  8/3581 (0.22%) 
Breast cancer female † 1  2/3576 (0.06%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Breast cancer in situ † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Breast cancer recurrent † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Breast cancer stage II † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Breast cancer stage III † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Bronchial carcinoma † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Cervix carcinoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  2/3581 (0.06%) 
Cervix carcinoma stage II † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  2/3581 (0.06%) 
Choroid melanoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Colon adenoma † 1  0/3576 (0.00%)  3/3581 (0.08%)  0/3576 (0.00%)  3/3581 (0.08%) 
Colon cancer † 1  0/3576 (0.00%)  0/3581 (0.00%)  3/3576 (0.08%)  1/3581 (0.03%) 
Colon cancer metastatic † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Colon neoplasm † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Colorectal adenocarcinoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Colorectal cancer † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Diffuse large B-cell lymphoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Endometrial adenocarcinoma † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Fibrous histiocytoma † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Gallbladder cancer † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Gastric cancer † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  2/3581 (0.06%) 
Glioblastoma multiforme † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Granular cell tumour † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Haemangioma † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hepatic cancer † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Hepatocellular carcinoma † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Intraductal proliferative breast lesion † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Intraocular melanoma † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Invasive ductal breast carcinoma † 1  0/3576 (0.00%)  3/3581 (0.08%)  1/3576 (0.03%)  4/3581 (0.11%) 
Large intestine benign neoplasm † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Laryngeal squamous cell carcinoma † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Lentigo maligna † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Lung adenocarcinoma † 1  1/3576 (0.03%)  0/3581 (0.00%)  3/3576 (0.08%)  1/3581 (0.03%) 
Lung adenocarcinoma metastatic † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  2/3581 (0.06%) 
Lung neoplasm malignant † 1  6/3576 (0.17%)  7/3581 (0.20%)  10/3576 (0.28%)  13/3581 (0.36%) 
Lymphoma † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Malignant melanoma in situ † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Malignant neoplasm of conjunctiva † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Mantle cell lymphoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Meningioma † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Meningioma benign † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  2/3581 (0.06%) 
Metastases to bone † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Metastases to liver † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  3/3581 (0.08%) 
Metastases to lymph nodes † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  2/3581 (0.06%) 
Metastases to pleura † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Metastatic bronchial carcinoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Metastatic malignant melanoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Nasopharyngeal cancer † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Neoplasm of appendix † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Neuroendocrine carcinoma of the skin † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Neurofibroma † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Non-Hodgkin's lymphoma † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Oesophageal carcinoma † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Oesophageal squamous cell carcinoma † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Oesophageal squamous cell carcinoma recurrent † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Ovarian adenoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Ovarian cancer † 1  1/3576 (0.03%)  1/3581 (0.03%)  3/3576 (0.08%)  3/3581 (0.08%) 
Ovarian cancer metastatic † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Paget's disease of nipple † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Pancoast's tumour † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pancreatic carcinoma † 1  0/3576 (0.00%)  2/3581 (0.06%)  0/3576 (0.00%)  3/3581 (0.08%) 
Pancreatic neuroendocrine tumour † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Papillary thyroid cancer † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Paranasal sinus benign neoplasm † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Phaeochromocytoma † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Pituitary tumour benign † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Plasma cell myeloma † 1  1/3576 (0.03%)  1/3581 (0.03%)  2/3576 (0.06%)  1/3581 (0.03%) 
Pyogenic granuloma † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Rectal adenocarcinoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Rectal cancer † 1  1/3576 (0.03%)  0/3581 (0.00%)  2/3576 (0.06%)  1/3581 (0.03%) 
Rectal cancer stage II † 1  1/3576 (0.03%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Rectosigmoid cancer † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Renal adenoma † 1  0/3576 (0.00%)  1/3581 (0.03%)  0/3576 (0.00%)  1/3581 (0.03%) 
Renal cancer † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Renal cell carcinoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Skin cancer † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Small cell lung cancer † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  1/3581 (0.03%) 
Small intestine adenocarcinoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  0/3576 (0.00%)  1/3581 (0.03%) 
Small intestine carcinoma † 1  0/3576 (0.00%)  0/3581 (0.00%)  1/3576 (0.03%)  0/3581 (0.00%) 
Squamous cell carcinoma † 1  2/3576 (0.06%)  1/3581 (0.03%)  2/3576 (0.06%)