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Trial record 1 of 1 for:    NCT01439880
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Open Label Study of Long Term Evaluation Against LDL-C Trial (OSLER)

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: NCT01439880
Recruitment Status : Completed
First Posted : September 23, 2011
Results First Posted : July 10, 2019
Last Update Posted : July 10, 2019
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hypercholesterolemia
Interventions Biological: Evolocumab
Other: Standard of care
Enrollment 1324
Recruitment Details

This extension study was conducted at 188 centers in 18 countries. Participants were enrolled from one of five eligible phase 2 parent studies: 20101154 (NCT01375777), 20101155 (NCT01380730), 20090158 (NCT01375751), 20090159 (NCT01375764), and 20110231 (NCT01652703).

Participants were enrolled from October 2011 to June 2013.

Pre-assignment Details Participants were randomized in a 2:1 ratio, irrespective of their treatment assignments during the phase 2 parent study, to either evolocumab plus standard of care (SOC) or SOC alone. Randomization was stratified by the treatment to which the participant was randomized to in the parent study, ie evolocumab or control.
Arm/Group Title Standard of Care Evolocumab + SOC
Hide Arm/Group Description

Participants randomized to receive standard of care (SOC) treatment for the first year of the extension study (SOC-controlled period).

At week 52 participants began treatment with evolocumab 420 mg QM for up to 4 years in the all-investigational product [all-IP] period.

Participants randomized to receive evolocumab 420 mg once a month plus standard of care for the first year of the extension study (SOC-controlled period).

At week 52 participants continued treatment with evolocumab 420 mg QM for up to 4 years in the all-IP period.

Period Title: SOC-controlled Period (Year 1)
Started 442 882
Received Evolocumab 0 881
Completed 398 822
Not Completed 44 60
Reason Not Completed
Withdrawal by Subject             24             38
Death             2             1
Sponsor Decision             0             1
Lost to Follow-up             10             5
Other             8             13
Reason Missing             0             2
Period Title: All-IP Period (Years 2 to 5)
Started 398 822
Received Evolocumab 374 777
Completed 328 682
Not Completed 70 140
Reason Not Completed
Lost to Follow-up             21             30
Withdrawal by Subject             30             66
Death             3             13
Sponsor Decision             1             0
Other             14             31
Reason Missing             1             0
Arm/Group Title Standard of Care Evolocumab + SOC Total
Hide Arm/Group Description Participants randomized to receive standard of care (SOC) treatment for the first year of the extension study (SOC-controlled period). Participants randomized to receive evolocumab 420 mg once a month plus standard of care for the first year of the extension study (SOC-controlled period). Total of all reporting groups
Overall Number of Baseline Participants 442 882 1324
Hide Baseline Analysis Population Description
The full analysis set included all randomized participants
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 442 participants 882 participants 1324 participants
57.6  (11.5) 56.9  (11.6) 57.1  (11.6)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 442 participants 882 participants 1324 participants
< 65 years
307
  69.5%
632
  71.7%
939
  70.9%
≥ 65 years
135
  30.5%
250
  28.3%
385
  29.1%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 442 participants 882 participants 1324 participants
Female
241
  54.5%
459
  52.0%
700
  52.9%
Male
201
  45.5%
423
  48.0%
624
  47.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 442 participants 882 participants 1324 participants
Hispanic or Latino
13
   2.9%
39
   4.4%
52
   3.9%
Not Hispanic or Latino
429
  97.1%
843
  95.6%
1272
  96.1%
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 442 participants 882 participants 1324 participants
American Indian or Alaska Native
3
   0.7%
1
   0.1%
4
   0.3%
Asian
87
  19.7%
168
  19.0%
255
  19.3%
Black or African American
24
   5.4%
54
   6.1%
78
   5.9%
Native Hawaiian or Other Pacific Islander
2
   0.5%
5
   0.6%
7
   0.5%
White
325
  73.5%
648
  73.5%
973
  73.5%
Other
1
   0.2%
4
   0.5%
5
   0.4%
Mixed Race
0
   0.0%
2
   0.2%
2
   0.2%
Region  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 442 participants 882 participants 1324 participants
North America
214
  48.4%
441
  50.0%
655
  49.5%
Europe
133
  30.1%
261
  29.6%
394
  29.8%
Asia Pacific
95
  21.5%
180
  20.4%
275
  20.8%
Parent Study Baseline Low-density Lipoprotein Cholesterol (LDL-C) Concentration  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 442 participants 882 participants 1324 participants
144.6  (37.4) 139.7  (36.7) 141.3  (37.0)
Stratification Factor: Parent Study Treatment Assignment   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 442 participants 882 participants 1324 participants
Evolocumab once monthly (QM)
193
  43.7%
387
  43.9%
580
  43.8%
Evolocumab every 2 weeks (Q2M)
129
  29.2%
256
  29.0%
385
  29.1%
No evolocumab
120
  27.1%
239
  27.1%
359
  27.1%
[1]
Measure Description:

Randomization was stratified by the treatment to which a participant was randomized to in the parent study, according to the following:

  • randomized to evolocumab every 2 weeks (Q2W)
  • randomized to evolocumab QM
  • not randomized to evolocumab
1.Primary Outcome
Title Number of Participants With Adverse Events
Hide Description Adverse event (AE) severity assessments were made using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grading, version 4.03, where grade 1 = mild AE, grade 2 = moderate AE, Grade 3 = severe AE, grade 4 = life-threatening AE and Grade 5 = death due to AE.
Time Frame 52 weeks in the SOC-controlled period and up to 4 years in the All-IP period; actual median duration of treatment in the All-IP period was 46.9 months.
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants (year 1) and randomized participants on study and who received at least 1 dose of evolocumab in the all-IP period (years 2-5).
Arm/Group Title SOC-controlled Period: Standard of Care SOC-controlled Period: Evolocumab + SOC All-IP Period: SOC / Evolocumab + SOC All-IP Period: Evolocumab + SOC / Evolocumab + SOC
Hide Arm/Group Description:
Participants randomized to receive standard of care (SOC) treatment for the first year of the extension study (SOC-controlled period).
Participants randomized to receive evolocumab 420 mg once a month plus standard of care for the first year of the extension study (SOC-controlled period).
At week 52 participants began treatment with evolocumab 420 mg QM for up to 4 years during the all-IP period.
At week 52 participants continued treatment with evolocumab 420 mg QM for another 4 years during the all-IP period.
Overall Number of Participants Analyzed 442 882 374 777
Measure Type: Count of Participants
Unit of Measure: Participants
All adverse events
327
  74.0%
728
  82.5%
342
  91.4%
718
  92.4%
Adverse events ≥ grade 3
46
  10.4%
99
  11.2%
111
  29.7%
229
  29.5%
Adverse events ≥ grade 4
2
   0.5%
11
   1.2%
8
   2.1%
28
   3.6%
Serious adverse events
30
   6.8%
72
   8.2%
76
  20.3%
172
  22.1%
AEs leading to discontinuation of evolocumab
0
   0.0%
28
   3.2%
16
   4.3%
27
   3.5%
Fatal adverse events
0
   0.0%
0
   0.0%
1
   0.3%
3
   0.4%
2.Secondary Outcome
Title Low-density Lipoprotein Cholesterol (LDL-C) Level at Week 24 and Week 52
Hide Description [Not Specified]
Time Frame Baseline of parent study and extension study weeks 24 and 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants randomized in study 20110110 and with available data at each time point.
Arm/Group Title Standard of Care Evolocumab + SOC Control in Parent Study: SOC Control in Parent Study: Evolocumab + SOC Evolocumab in Parent Study: SOC Evolocumab in Parent Study: Evolocumab + SOC
Hide Arm/Group Description:
Participants randomized to receive standard of care (SOC) treatment for the first year of the extension study (SOC-controlled period).
Participants randomized to receive evolocumab 420 mg once a month plus standard of care for the first year of the extension study (SOC-controlled period).
Participants who received a control treatment in the parent study received standard of care treatment for the first year of the extension study.
Participants who received a control treatment in the parent study received subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.
Participants who received evolocumab in the parent study received standard of care treatment during the first year of the extension study.
Participants who received evolocumab in the parent study received subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.
Overall Number of Participants Analyzed 442 882 120 239 322 643
Mean (Standard Deviation)
Unit of Measure: mg/dL
Parent Study Baseline Number Analyzed 442 participants 882 participants 120 participants 239 participants 322 participants 643 participants
144.6  (37.4) 139.7  (36.7) 147.7  (34.3) 139.5  (33.6) 143.4  (38.5) 139.8  (37.8)
Week 24 Number Analyzed 416 participants 852 participants 113 participants 232 participants 303 participants 620 participants
136.9  (41.5) 64.1  (33.3) 142.5  (44.7) 63.9  (34.6) 134.8  (40.2) 64.2  (32.9)
Week 52 Number Analyzed 399 participants 826 participants 113 participants 224 participants 286 participants 602 participants
140.5  (40.0) 65.0  (34.4) 143.1  (39.8) 64.1  (33.2) 139.4  (40.1) 65.3  (34.9)
3.Secondary Outcome
Title Non-high-density Lipoprotein Cholesterol (Non-HDL-C) Level at Week 24 and Week 52
Hide Description [Not Specified]
Time Frame Baseline of parent study and extension study weeks 24 and 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants randomized in the extension study 20110110 and with available data at each time point.
Arm/Group Title Standard of Care Evolocumab + SOC Control in Parent Study: SOC Control in Parent Study: Evolocumab + SOC Evolocumab in Parent Study: SOC Evolocumab in Parent Study: Evolocumab + SOC
Hide Arm/Group Description:
Participants randomized to receive standard of care (SOC) treatment for the first year of the extension study (SOC-controlled period).
Participants randomized to receive evolocumab 420 mg once a month plus standard of care for the first year of the extension study (SOC-controlled period).
Participants who received a control treatment in the parent study received standard of care treatment for the first year of the extension study.
Participants who received a control treatment in the parent study received subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.
Participants who received evolocumab in the parent study received standard of care treatment during the first year of the extension study.
Participants who received evolocumab in the parent study received subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.
Overall Number of Participants Analyzed 442 882 120 239 322 643
Mean (Standard Deviation)
Unit of Measure: mg/dL
Parent Study Baseline Number Analyzed 442 participants 882 participants 120 participants 239 participants 322 participants 643 participants
170.7  (43.0) 165.1  (40.9) 173.8  (39.6) 165.5  (38.9) 169.6  (44.2) 165.0  (41.7)
Week 24 Number Analyzed 416 participants 852 participants 113 participants 232 participants 303 participants 620 participants
161.4  (45.5) 84.3  (37.7) 166.9  (47.5) 84.3  (39.0) 159.4  (44.6) 84.3  (37.3)
Week 52 Number Analyzed 399 participants 825 participants 113 participants 224 participants 286 participants 601 participants
164.9  (44.5) 85.3  (39.0) 168.8  (45.3) 85.0  (38.4) 163.4  (44.1) 85.4  (39.2)
4.Secondary Outcome
Title Apolipoprotein B Level at Week 24 and Week 52
Hide Description [Not Specified]
Time Frame Baseline of parent study and extension study weeks 24 and 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants randomized in the extension study 20110110 and with available data at each time point.
Arm/Group Title Standard of Care Evolocumab + SOC Control in Parent Study: SOC Control in Parent Study: Evolocumab + SOC Evolocumab in Parent Study: SOC Evolocumab in Parent Study: Evolocumab + SOC
Hide Arm/Group Description:
Participants randomized to receive standard of care (SOC) treatment for the first year of the extension study (SOC-controlled period).
Participants randomized to receive evolocumab 420 mg once a month plus standard of care for the first year of the extension study (SOC-controlled period).
Participants who received a control treatment in the parent study received standard of care treatment for the first year of the extension study.
Participants who received a control treatment in the parent study received subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.
Participants who received evolocumab in the parent study received standard of care treatment during the first year of the extension study.
Participants who received evolocumab in the parent study received subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.
Overall Number of Participants Analyzed 442 882 120 239 322 643
Mean (Standard Deviation)
Unit of Measure: mg/dL
Parent Study Baseline Number Analyzed 442 participants 882 participants 120 participants 239 participants 322 participants 643 participants
113.2  (25.3) 110.4  (23.8) 115.4  (23.1) 110.3  (22.4) 112.4  (26.0) 110.4  (24.3)
Week 24 Number Analyzed 416 participants 852 participants 113 participants 232 participants 303 participants 620 participants
107.9  (26.3) 60.8  (23.3) 110.5  (27.0) 60.7  (23.9) 106.9  (26.0) 60.9  (23.1)
Week 52 Number Analyzed 401 participants 834 participants 113 participants 227 participants 288 participants 607 participants
109.5  (26.8) 61.6  (23.5) 110.7  (26.3) 61.7  (23.0) 109.1  (27.0) 61.6  (23.7)
5.Secondary Outcome
Title Total Cholesterol/HDL-C Ratio at Week 24 and Week 52
Hide Description [Not Specified]
Time Frame Baseline of parent study and extension study weeks 24 and 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants randomized in the extension study 20110110 and with available data at each time point.
Arm/Group Title Standard of Care Evolocumab + SOC Control in Parent Study: SOC Control in Parent Study: Evolocumab + SOC Evolocumab in Parent Study: SOC Evolocumab in Parent Study: Evolocumab + SOC
Hide Arm/Group Description:
Participants randomized to receive standard of care (SOC) treatment for the first year of the extension study (SOC-controlled period).
Participants randomized to receive evolocumab 420 mg once a month plus standard of care for the first year of the extension study (SOC-controlled period).
Participants who received a control treatment in the parent study received standard of care treatment for the first year of the extension study.
Participants who received a control treatment in the parent study received subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.
Participants who received evolocumab in the parent study received standard of care treatment during the first year of the extension study.
Participants who received evolocumab in the parent study received subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.
Overall Number of Participants Analyzed 442 882 120 239 322 643
Mean (Standard Deviation)
Unit of Measure: ratio
Parent Study Baseline Number Analyzed 442 participants 882 participants 120 participants 239 participants 322 participants 643 participants
4.516  (1.617) 4.386  (1.393) 4.458  (1.345) 4.388  (1.340) 4.538  (1.708) 4.386  (1.413)
Week 24 Number Analyzed 416 participants 852 participants 113 participants 232 participants 303 participants 620 participants
4.198  (1.536) 2.603  (0.978) 4.192  (1.408) 2.594  (0.970) 4.201  (1.584) 2.607  (0.982)
Week 52 Number Analyzed 399 participants 825 participants 113 participants 224 participants 286 participants 601 participants
4.277  (1.652) 2.626  (1.025) 4.252  (1.434) 2.622  (1.033) 4.286  (1.733) 2.628  (1.023)
6.Secondary Outcome
Title Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24 and Week 52
Hide Description [Not Specified]
Time Frame Baseline of parent study and extension study weeks 24 and 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants randomized in the extension study 20110110 and with available data at each time point.
Arm/Group Title Standard of Care Evolocumab + SOC Control in Parent Study: SOC Control in Parent Study: Evolocumab + SOC Evolocumab in Parent Study: SOC Evolocumab in Parent Study: Evolocumab + SOC
Hide Arm/Group Description:
Participants randomized to receive standard of care (SOC) treatment for the first year of the extension study (SOC-controlled period).
Participants randomized to receive evolocumab 420 mg once a month plus standard of care for the first year of the extension study (SOC-controlled period).
Participants who received a control treatment in the parent study received standard of care treatment for the first year of the extension study.
Participants who received a control treatment in the parent study received subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.
Participants who received evolocumab in the parent study received standard of care treatment during the first year of the extension study.
Participants who received evolocumab in the parent study received subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.
Overall Number of Participants Analyzed 442 882 120 239 322 643
Mean (Standard Deviation)
Unit of Measure: ratio
Parent Study Baseline Number Analyzed 442 participants 882 participants 120 participants 239 participants 322 participants 643 participants
0.759  (0.237) 0.739  (0.217) 0.764  (0.201) 0.735  (0.212) 0.757  (0.249) 0.741  (0.218)
Week 24 Number Analyzed 416 participants 852 participants 113 participants 232 participants 303 participants 620 participants
0.717  (0.242) 0.386  (0.178) 0.715  (0.222) 0.385  (0.183) 0.718  (0.250) 0.387  (0.176)
Week 52 Number Analyzed 401 participants 834 participants 113 participants 227 participants 288 participants 607 participants
0.726  (0.256) 0.394  (0.185) 0.719  (0.216) 0.393  (0.186) 0.729  (0.271) 0.394  (0.185)
Time Frame 52 weeks in the SOC-controlled period and up to 4 years in the All-IP period; median duration of treatment in the All-IP period was 46.9 months.
Adverse Event Reporting Description

Adverse events are reported for all randomized participants in the SOC-controlled period (year 1) and for all participants who entered the All-IP period (years 2-5).

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

 
Arm/Group Title SOC-controlled Period: SOC SOC-controlled Period: Evolocumab + SOC All-IP Period: SOC / Evolocumab All-IP Period: Evolocumab + SOC / Evolocumab All-IP Period: Total
Hide Arm/Group Description Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period). Participants received evolocumab 420 mg once a month for the first year of the study (SOC-controlled period). At week 52 participants began treatment with evolocumab 420 mg QM for up to 4 years during the all-IP period. At week 52 participants continued treatment with evolocumab 420 mg QM for another 4 years during the all-IP period. All participants in the All-IP period who received evolocumab 420 mg QM for up to 4 years.
All-Cause Mortality
SOC-controlled Period: SOC SOC-controlled Period: Evolocumab + SOC All-IP Period: SOC / Evolocumab All-IP Period: Evolocumab + SOC / Evolocumab All-IP Period: Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/442 (0.45%)   1/882 (0.11%)   3/398 (0.75%)   13/822 (1.58%)   16/1220 (1.31%) 
Hide Serious Adverse Events
SOC-controlled Period: SOC SOC-controlled Period: Evolocumab + SOC All-IP Period: SOC / Evolocumab All-IP Period: Evolocumab + SOC / Evolocumab All-IP Period: Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   30/442 (6.79%)   72/882 (8.16%)   78/398 (19.60%)   181/822 (22.02%)   259/1220 (21.23%) 
Blood and lymphatic system disorders           
Anaemia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Febrile neutropenia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Iron deficiency anaemia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Cardiac disorders           
Acute coronary syndrome  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Angina pectoris  1  2/442 (0.45%)  4/882 (0.45%)  1/398 (0.25%)  9/822 (1.09%)  10/1220 (0.82%) 
Angina unstable  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Aortic valve disease  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Aortic valve disease mixed  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Aortic valve incompetence  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Aortic valve sclerosis  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Aortic valve stenosis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Arteriosclerosis coronary artery  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Atrial fibrillation  1  1/442 (0.23%)  1/882 (0.11%)  2/398 (0.50%)  7/822 (0.85%)  9/1220 (0.74%) 
Atrial flutter  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Atrial thrombosis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Bradycardia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Cardiac arrest  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Cardiac failure  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Cardiac failure congestive  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Cardiogenic shock  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Cardiopulmonary failure  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Coronary artery disease  1  0/442 (0.00%)  1/882 (0.11%)  2/398 (0.50%)  4/822 (0.49%)  6/1220 (0.49%) 
Coronary artery embolism  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Coronary artery occlusion  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Coronary artery stenosis  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  2/822 (0.24%)  3/1220 (0.25%) 
Mitral valve disease  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Mitral valve disease mixed  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Mitral valve incompetence  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Myocardial ischaemia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Nodal rhythm  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Pericarditis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Supraventricular tachycardia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Ventricular extrasystoles  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Ventricular tachycardia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Ear and labyrinth disorders           
Sudden hearing loss  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Vertigo positional  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Endocrine disorders           
Thyroid mass  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Thyroiditis acute  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Eye disorders           
Cataract  1  0/442 (0.00%)  0/882 (0.00%)  2/398 (0.50%)  2/822 (0.24%)  4/1220 (0.33%) 
Cataract cortical  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Corneal defect  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Eyelid ptosis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Keratitis  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Gastrointestinal disorders           
Abdominal discomfort  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Abdominal pain  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Abdominal pain upper  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Anal fistula  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Brunner's gland hyperplasia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Colitis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Constipation  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Diarrhoea  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Dysphagia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Faecaloma  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Faeces discoloured  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Gastritis  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Gastrooesophageal reflux disease  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Haemorrhoidal haemorrhage  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Haemorrhoids  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Hiatus hernia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Ileus paralytic  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Impaired gastric emptying  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Inguinal hernia  1  1/442 (0.23%)  0/882 (0.00%)  2/398 (0.50%)  0/822 (0.00%)  2/1220 (0.16%) 
Intestinal ischaemia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Intestinal obstruction  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Large intestine polyp  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  2/822 (0.24%)  3/1220 (0.25%) 
Lumbar hernia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Nausea  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Obstructive pancreatitis  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Oesophageal spasm  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Pancreatitis  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Retroperitoneal haematoma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Splenic artery aneurysm  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Tooth impacted  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
General disorders           
Chest discomfort  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Chest pain  1  1/442 (0.23%)  4/882 (0.45%)  1/398 (0.25%)  6/822 (0.73%)  7/1220 (0.57%) 
Fatigue  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Hypothermia  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Mass  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Nodule  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Non-cardiac chest pain  1  1/442 (0.23%)  4/882 (0.45%)  0/398 (0.00%)  7/822 (0.85%)  7/1220 (0.57%) 
Organ failure  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Pain  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Hepatobiliary disorders           
Autoimmune hepatitis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Biliary dyskinesia  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Cholecystitis  1  0/442 (0.00%)  0/882 (0.00%)  2/398 (0.50%)  1/822 (0.12%)  3/1220 (0.25%) 
Cholecystitis acute  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  4/822 (0.49%)  4/1220 (0.33%) 
Cholelithiasis  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  4/822 (0.49%)  5/1220 (0.41%) 
Drug-induced liver injury  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Hepatic function abnormal  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Hepatotoxicity  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Jaundice  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Immune system disorders           
Contrast media allergy  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Drug hypersensitivity  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Infections and infestations           
Abscess limb  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Anal abscess  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Appendiceal abscess  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Appendicitis  1  1/442 (0.23%)  5/882 (0.57%)  2/398 (0.50%)  3/822 (0.36%)  5/1220 (0.41%) 
Arthritis bacterial  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Arthritis infective  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Bacterial pyelonephritis  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Bronchitis  1  0/442 (0.00%)  0/882 (0.00%)  2/398 (0.50%)  2/822 (0.24%)  4/1220 (0.33%) 
Bursitis infective  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Cellulitis  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Cellulitis staphylococcal  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Chronic sinusitis  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Clostridial infection  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Clostridium difficile colitis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Cystitis  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Diverticulitis  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Endocarditis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Erysipelas  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Escherichia sepsis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Gastroenteritis  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Gastroenteritis bacterial  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Groin abscess  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Herpes zoster  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Infective spondylitis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Joint abscess  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Meningitis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Ophthalmic herpes simplex  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Osteomyelitis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Pneumonia  1  0/442 (0.00%)  3/882 (0.34%)  2/398 (0.50%)  4/822 (0.49%)  6/1220 (0.49%) 
Pneumonia bacterial  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Postoperative wound infection  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Pyelonephritis  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  3/822 (0.36%)  4/1220 (0.33%) 
Respiratory tract infection  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Rocky mountain spotted fever  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Sepsis  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Skin infection  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Streptococcal sepsis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Subcutaneous abscess  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Upper respiratory tract infection  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Urinary tract infection  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  4/822 (0.49%)  4/1220 (0.33%) 
Injury, poisoning and procedural complications           
Anaesthetic complication  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Ankle fracture  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Cardiac contusion  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Clavicle fracture  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Concussion  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Contusion  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Fall  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Femur fracture  1  0/442 (0.00%)  0/882 (0.00%)  2/398 (0.50%)  2/822 (0.24%)  4/1220 (0.33%) 
Foot fracture  1  0/442 (0.00%)  0/882 (0.00%)  2/398 (0.50%)  0/822 (0.00%)  2/1220 (0.16%) 
Hip fracture  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Intervertebral disc injury  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Joint dislocation  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Laceration  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Lower limb fracture  1  0/442 (0.00%)  2/882 (0.23%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Lumbar vertebral fracture  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Meniscus injury  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Multiple fractures  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Muscle rupture  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Pelvic fracture  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Post procedural haematoma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Post procedural haematuria  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Post procedural haemorrhage  1  1/442 (0.23%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Procedural complication  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Procedural nausea  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Procedural pain  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Procedural vomiting  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Pubis fracture  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Pulmonary contusion  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Rib fracture  1  0/442 (0.00%)  0/882 (0.00%)  2/398 (0.50%)  1/822 (0.12%)  3/1220 (0.25%) 
Scapula fracture  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Spinal compression fracture  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Subdural haematoma  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Tendon injury  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Tendon rupture  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Tibia fracture  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Toxicity to various agents  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Traumatic intracranial haemorrhage  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Ulna fracture  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Upper limb fracture  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Urinary retention postoperative  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Wound  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Wound dehiscence  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Wrist fracture  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  3/822 (0.36%)  4/1220 (0.33%) 
Investigations           
Electrocardiogram ST segment abnormal  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
HIV test positive  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Heart rate increased  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Hepatic enzyme increased  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Platelet count decreased  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Weight decreased  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Metabolism and nutrition disorders           
Dehydration  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Diabetes mellitus  1  0/442 (0.00%)  3/882 (0.34%)  2/398 (0.50%)  0/822 (0.00%)  2/1220 (0.16%) 
Diabetic ketoacidosis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Fluid retention  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Hyperglycaemia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Hypoglycaemia  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Hyponatraemia  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Malnutrition  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Type 2 diabetes mellitus  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Musculoskeletal and connective tissue disorders           
Arthralgia  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  3/822 (0.36%)  3/1220 (0.25%) 
Arthritis  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Back pain  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  3/822 (0.36%)  4/1220 (0.33%) 
Bursitis  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Chondrocalcinosis pyrophosphate  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Chondropathy  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Costochondritis  1  0/442 (0.00%)  1/882 (0.11%)  2/398 (0.50%)  1/822 (0.12%)  3/1220 (0.25%) 
Dupuytren's contracture  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Foot deformity  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Intervertebral disc disorder  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Intervertebral disc protrusion  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Lumbar spinal stenosis  1  0/442 (0.00%)  0/882 (0.00%)  2/398 (0.50%)  0/822 (0.00%)  2/1220 (0.16%) 
Muscular weakness  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Musculoskeletal chest pain  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Musculoskeletal pain  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Myalgia  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Osteoarthritis  1  1/442 (0.23%)  3/882 (0.34%)  5/398 (1.26%)  9/822 (1.09%)  14/1220 (1.15%) 
Osteoporosis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Pain in extremity  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Rhabdomyolysis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Rotator cuff syndrome  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Spinal column stenosis  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  3/822 (0.36%)  4/1220 (0.33%) 
Spinal osteoarthritis  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Spinal pain  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Synovial cyst  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Tendonitis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Acute leukaemia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Adenocarcinoma gastric  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Adenocarcinoma of colon  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Adenoma benign  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Anal squamous cell carcinoma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
B-cell lymphoma  1  0/442 (0.00%)  0/882 (0.00%)  2/398 (0.50%)  1/822 (0.12%)  3/1220 (0.25%) 
Benign neoplasm of bladder  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Bladder cancer  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Bladder neoplasm  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Bladder transitional cell carcinoma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Breast cancer  1  1/442 (0.23%)  0/882 (0.00%)  1/398 (0.25%)  5/822 (0.61%)  6/1220 (0.49%) 
Cholangiocarcinoma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Chronic lymphocytic leukaemia  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Colon adenoma  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Colon cancer  1  1/442 (0.23%)  0/882 (0.00%)  2/398 (0.50%)  1/822 (0.12%)  3/1220 (0.25%) 
Diffuse large B-cell lymphoma  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Gastric cancer  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Hairy cell leukaemia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Hepatic cancer metastatic  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Intraductal papilloma of breast  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Intraductal proliferative breast lesion  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Kaposi's sarcoma  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Lung adenocarcinoma  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Lung neoplasm malignant  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Lymphoma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Mantle cell lymphoma stage IV  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Meningioma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Metastases to lung  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Metastases to lymph nodes  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Myxoid liposarcoma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Oesophageal carcinoma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Pancreatic carcinoma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Papillary thyroid cancer  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Prostate cancer  1  0/442 (0.00%)  1/882 (0.11%)  2/398 (0.50%)  4/822 (0.49%)  6/1220 (0.49%) 
Rectal adenoma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Rectal cancer  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Small cell lung cancer  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Small cell lung cancer metastatic  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Squamous cell carcinoma  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Squamous cell carcinoma of lung  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Thyroid adenoma  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Uterine cancer  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Uterine leiomyoma  1  1/442 (0.23%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Nervous system disorders           
Ataxia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Brain stem haemorrhage  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Carotid artery stenosis  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Cerebral thrombosis  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Cerebrovascular accident  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Cervical radiculopathy  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Dizziness  1  1/442 (0.23%)  0/882 (0.00%)  2/398 (0.50%)  0/822 (0.00%)  2/1220 (0.16%) 
Dizziness postural  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Encephalopathy  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Facial paralysis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Generalised tonic-clonic seizure  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Guillain-Barre syndrome  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Haemorrhage intracranial  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Headache  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Lumbar radiculopathy  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Migraine  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Motor neurone disease  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Myelopathy  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Presyncope  1  0/442 (0.00%)  2/882 (0.23%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Sciatica  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Spinal claudication  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Syncope  1  0/442 (0.00%)  2/882 (0.23%)  0/398 (0.00%)  4/822 (0.49%)  4/1220 (0.33%) 
Tension headache  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Transient ischaemic attack  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Tremor  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Trigeminal neuralgia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Vertebrobasilar insufficiency  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Pregnancy, puerperium and perinatal conditions           
Abortion spontaneous  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Ectopic pregnancy  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Psychiatric disorders           
Alcohol abuse  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Alcohol withdrawal syndrome  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Anxiety  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Confusional state  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Delirium  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Depression  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Hallucination  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Mental status changes  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Psychotic disorder  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Suicidal ideation  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Renal and urinary disorders           
Acute kidney injury  1  1/442 (0.23%)  1/882 (0.11%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Bladder prolapse  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Calculus bladder  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Chronic kidney disease  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Hydronephrosis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Nephrolithiasis  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  3/822 (0.36%)  4/1220 (0.33%) 
Renal artery stenosis  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Renal colic  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Renal failure  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Ureterolithiasis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Urinary incontinence  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Reproductive system and breast disorders           
Benign prostatic hyperplasia  1  0/442 (0.00%)  2/882 (0.23%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Cystocele  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Menorrhagia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Postmenopausal haemorrhage  1  1/442 (0.23%)  0/882 (0.00%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Prostatitis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Uterine prolapse  1  1/442 (0.23%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Respiratory, thoracic and mediastinal disorders           
Asthma  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Chronic obstructive pulmonary disease  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  4/822 (0.49%)  4/1220 (0.33%) 
Dyspnoea  1  0/442 (0.00%)  0/882 (0.00%)  2/398 (0.50%)  2/822 (0.24%)  4/1220 (0.33%) 
Dyspnoea exertional  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Epistaxis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Haemoptysis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Interstitial lung disease  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  1/822 (0.12%)  2/1220 (0.16%) 
Laryngeal polyp  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Pharyngeal oedema  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Pleurisy  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Pulmonary embolism  1  2/442 (0.45%)  1/882 (0.11%)  1/398 (0.25%)  4/822 (0.49%)  5/1220 (0.41%) 
Pulmonary granuloma  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Pulmonary oedema  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Respiratory failure  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Sinus polyp  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Vocal cord polyp  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Skin and subcutaneous tissue disorders           
Urticaria  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Surgical and medical procedures           
Cholecystectomy  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Knee arthroplasty  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Medical device removal  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Vascular disorders           
Accelerated hypertension  1  0/442 (0.00%)  1/882 (0.11%)  0/398 (0.00%)  0/822 (0.00%)  0/1220 (0.00%) 
Aortic aneurysm  1  0/442 (0.00%)  0/882 (0.00%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Aortic stenosis  1  0/442 (0.00%)  1/882 (0.11%)  1/398 (0.25%)  0/822 (0.00%)  1/1220 (0.08%) 
Deep vein thrombosis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  2/822 (0.24%)  2/1220 (0.16%) 
Hypertension  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Hypertensive crisis  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Peripheral arterial occlusive disease  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Peripheral ischaemia  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
Peripheral vascular disorder  1  0/442 (0.00%)  0/882 (0.00%)  0/398 (0.00%)  1/822 (0.12%)  1/1220 (0.08%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
SOC-controlled Period: SOC SOC-controlled Period: Evolocumab + SOC All-IP Period: SOC / Evolocumab All-IP Period: Evolocumab + SOC / Evolocumab All-IP Period: Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   217/442 (49.10%)   513/882 (58.16%)   311/398 (78.14%)   626/822 (76.16%)   937/1220 (76.80%) 
Gastrointestinal disorders           
Diarrhoea  1  11/442 (2.49%)  41/882 (4.65%)  33/398 (8.29%)  61/822 (7.42%)  94/1220 (7.70%) 
Gastrooesophageal reflux disease  1  13/442 (2.94%)  23/882 (2.61%)  20/398 (5.03%)  32/822 (3.89%)  52/1220 (4.26%) 
Nausea  1  4/442 (0.90%)  23/882 (2.61%)  23/398 (5.78%)  32/822 (3.89%)  55/1220 (4.51%) 
General disorders           
Fatigue  1  5/442 (1.13%)  31/882 (3.51%)  16/398 (4.02%)  43/822 (5.23%)  59/1220 (4.84%) 
Infections and infestations           
Bronchitis  1  17/442 (3.85%)  48/882 (5.44%)  40/398 (10.05%)  94/822 (11.44%)  134/1220 (10.98%) 
Cystitis  1  9/442 (2.04%)  15/882 (1.70%)  25/398 (6.28%)  39/822 (4.74%)  64/1220 (5.25%) 
Influenza  1  24/442 (5.43%)  57/882 (6.46%)  47/398 (11.81%)  81/822 (9.85%)  128/1220 (10.49%) 
Nasopharyngitis  1  64/442 (14.48%)  148/882 (16.78%)  122/398 (30.65%)  236/822 (28.71%)  358/1220 (29.34%) 
Sinusitis  1  15/442 (3.39%)  32/882 (3.63%)  31/398 (7.79%)  68/822 (8.27%)  99/1220 (8.11%) 
Upper respiratory tract infection  1  29/442 (6.56%)  72/882 (8.16%)  57/398 (14.32%)  118/822 (14.36%)  175/1220 (14.34%) 
Injury, poisoning and procedural complications           
Contusion  1  10/442 (2.26%)  15/882 (1.70%)  25/398 (6.28%)  35/822 (4.26%)  60/1220 (4.92%) 
Procedural pain  1  4/442 (0.90%)  4/882 (0.45%)  20/398 (5.03%)  23/822 (2.80%)  43/1220 (3.52%) 
Musculoskeletal and connective tissue disorders           
Arthralgia  1  18/442 (4.07%)  59/882 (6.69%)  63/398 (15.83%)  109/822 (13.26%)  172/1220 (14.10%) 
Back pain  1  22/442 (4.98%)  62/882 (7.03%)  51/398 (12.81%)  117/822 (14.23%)  168/1220 (13.77%) 
Muscle spasms  1  10/442 (2.26%)  25/882 (2.83%)  21/398 (5.28%)  39/822 (4.74%)  60/1220 (4.92%) 
Musculoskeletal pain  1  12/442 (2.71%)  28/882 (3.17%)  19/398 (4.77%)  62/822 (7.54%)  81/1220 (6.64%) 
Osteoarthritis  1  4/442 (0.90%)  22/882 (2.49%)  27/398 (6.78%)  54/822 (6.57%)  81/1220 (6.64%) 
Pain in extremity  1  14/442 (3.17%)  44/882 (4.99%)  32/398 (8.04%)  70/822 (8.52%)  102/1220 (8.36%) 
Nervous system disorders           
Dizziness  1  12/442 (2.71%)  18/882 (2.04%)  20/398 (5.03%)  51/822 (6.20%)  71/1220 (5.82%) 
Headache  1  12/442 (2.71%)  54/882 (6.12%)  28/398 (7.04%)  44/822 (5.35%)  72/1220 (5.90%) 
Respiratory, thoracic and mediastinal disorders           
Cough  1  19/442 (4.30%)  41/882 (4.65%)  40/398 (10.05%)  77/822 (9.37%)  117/1220 (9.59%) 
Oropharyngeal pain  1  10/442 (2.26%)  24/882 (2.72%)  14/398 (3.52%)  42/822 (5.11%)  56/1220 (4.59%) 
Vascular disorders           
Hypertension  1  20/442 (4.52%)  52/882 (5.90%)  40/398 (10.05%)  99/822 (12.04%)  139/1220 (11.39%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Amgen Inc.
Phone: 866-572-6436
EMail: medinfo@amgen.com
Publications:
Layout table for additonal information
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01439880    
Other Study ID Numbers: 20110110
2011-001915-29 ( EudraCT Number )
First Submitted: September 22, 2011
First Posted: September 23, 2011
Results First Submitted: June 17, 2019
Results First Posted: July 10, 2019
Last Update Posted: July 10, 2019