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Clinical Trial Results:
A Multicenter, Controlled, Open-label Extension (OLE) Study to Assess the Long-term Safety and Efficacy of Evolocumab (AMG 145)

Summary
EudraCT number	2011-001915-29
Trial protocol	FI SE NO BE HU GB NL DK DE ES CZ
Global end of trial date	20 Jun 2018

Results information
Results version number	v1(current)
This version publication date	04 Jul 2019
First version publication date	04 Jul 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

20110110

ISRCTN number

-

US NCT number

NCT01439880

WHO universal trial number (UTN)

-

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

20 Jun 2018

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

20 Jun 2018

Was the trial ended prematurely?

No

Main objective of the trial

The main objective was to characterize the safety and tolerability of long-term administration of evolocumab.

Protection of trial subjects

This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, and Food and Drug Administration (FDA) regulations and guidelines set forth in 21 Code of Federal Regulation Parts 11, 50, 54, 56, and 312. The study and all amendments were reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) at each center. The investigator or their designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

07 Oct 2011

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 156

Country: Number of subjects enrolled

United States: 499

Country: Number of subjects enrolled

Belgium: 31

Country: Number of subjects enrolled

Czech Republic: 44

Country: Number of subjects enrolled

Denmark: 182

Country: Number of subjects enrolled

Finland: 7

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Hungary: 36

Country: Number of subjects enrolled

Netherlands: 25

Country: Number of subjects enrolled

Norway: 14

Country: Number of subjects enrolled

Spain: 35

Country: Number of subjects enrolled

Sweden: 15

Country: Number of subjects enrolled

United Kingdom: 1

Country: Number of subjects enrolled

Australia: 21

Country: Number of subjects enrolled

Hong Kong: 4

Country: Number of subjects enrolled

Japan: 219

Country: Number of subjects enrolled

Singapore: 1

Country: Number of subjects enrolled

South Africa: 30

Worldwide total number of subjects

1324

EEA total number of subjects

394

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

939

From 65 to 84 years

385

85 years and over

0

Subject disposition

Top of page

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 (2011-001544-30), 20101155 (2011-001527-20), 20090158 (2011-001528-39), 20090159 (2011-001529-26), and 20110231. Participants were enrolled from October 2011 to June 2013

Screening 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.

Period 1 title

SOC-controlled Period (Year 1)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Standard of Care

Arm description

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

Arm type

Standard of care

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Evolocumab + SOC

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Evolocumab

Investigational medicinal product code

AMG 145

Other name

Repatha

Pharmaceutical forms

Solution for injection, Solution for injection in pre-filled pen, Solution for injection in cartridge

Routes of administration

Subcutaneous use

Dosage and administration details

Administered by subcutaneous injection once a month.

Number of subjects in period 1	Standard of Care	Evolocumab + SOC
Started	442	882
Received Evolocumab	0 ^[1]	881
Completed	398	822
Not completed	44	60
Adverse event, serious fatal	2	1
Reason Missing	-	2
Consent withdrawn by subject	24	38
Other	8	13
Sponsor Decision	-	1
Lost to follow-up	10	5

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants in the Standard of Care group did not receive evolocumab in the SOC-controlled Period

Period 2 title

All-IP Period (Years 2 to 5)

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

SOC / Evolocumab

Arm description

At week 52 participants began treatment with evolocumab 420 mg once a month (QM) for up to 4 years during the all-investigational product [all-IP] period.

Arm type

Experimental

Investigational medicinal product name

Evolocumab

Investigational medicinal product code

AMG 145

Other name

Repatha

Pharmaceutical forms

Solution for injection in pre-filled pen, Solution for injection, Solution for injection in cartridge

Routes of administration

Subcutaneous use

Dosage and administration details

Administered by subcutaneous injection once a month.

Evolocumab + SOC / Evolocumab

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Evolocumab

Investigational medicinal product code

AMG 145

Other name

Repatha

Pharmaceutical forms

Solution for injection in pre-filled pen, Solution for injection, Solution for injection in cartridge

Routes of administration

Subcutaneous use

Dosage and administration details

Administered by subcutaneous injection once a month.

Number of subjects in period 2	SOC / Evolocumab	Evolocumab + SOC / Evolocumab
Started	398	822
Received Evolocumab	374	777
Completed	328	682
Not completed	70	140
Adverse event, serious fatal	3	13
Reason Missing	1	-
Consent withdrawn by subject	30	66
Other	14	31
Sponsor Decision	1	-
Lost to follow-up	21	30

Baseline characteristics

Top of page

Reporting group title

Standard of Care

Reporting group description

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

Reporting group title

Evolocumab + SOC

Reporting group description

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

Reporting group values	Standard of Care	Evolocumab + SOC	Total
Number of subjects	442	882	1324
Age, Customized
Units: Subjects
< 65 years	307	632	939
≥ 65 years	135	250	385
Age Continuous
Units: years
arithmetic mean (standard deviation)	57.6 ( 11.5 )	56.9 ( 11.6 )	-
Sex: Female, Male
Units: Subjects
Female	241	459	700
Male	201	423	624
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	3	1	4
Asian	87	168	255
Black or African American	24	54	78
Native Hawaiian or Other Pacific Islander	2	5	7
White	325	648	973
Other	1	4	5
Mixed Race	0	2	2
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	13	39	52
Not Hispanic or Latino	429	843	1272
Unknown or Not Reported	0	0	0
Region
Units: Subjects
North America	214	441	655
Europe	133	261	394
Asia Pacific	95	180	275
Stratification Factor: Parent Study Treatment Assignment
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
Units: Subjects
Evolocumab once monthly (QM)	193	387	580
Evolocumab every 2 weeks (Q2M)	129	256	385
No evolocumab	120	239	359
Parent Study Baseline Low-density Lipoprotein Cholesterol (LDL-C) Concentration
Units: mg/dL
arithmetic mean (standard deviation)	144.6 ( 37.4 )	139.7 ( 36.7 )	-

End points

Top of page

Reporting group title

Standard of Care

Reporting group description

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

Reporting group title

Evolocumab + SOC

Reporting group description

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

Reporting group title

SOC / Evolocumab

Reporting group description

At week 52 participants began treatment with evolocumab 420 mg once a month (QM) for up to 4 years during the all-investigational product [all-IP] period.

Reporting group title

Evolocumab + SOC / Evolocumab

Reporting group description

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

Subject analysis set title

Control in Parent Study: SOC

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who were randomized to a control treatment in the parent study were randomized to receive standard of care treatment for the first year of the extension study.

Subject analysis set title

Control in Parent Study: Evolocumab + SOC

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who were randomized to a control treatment in the parent study were randomized to receive subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.

Subject analysis set title

Evolocumab in Parent Study: SOC

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who were randomized to evolocumab in the parent study were randomized to receive standard of care treatment during the first year of the extension study.

Subject analysis set title

Evolocumab in Parent Study: Evolocumab + SOC

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who were randomized to evolocumab in the parent study were randomized to receive subcutaneous evolocumab 420 mg QM plus standard of care during the first year of the extension study.

Primary: Number of Participants with Adverse Events

Top of page

End point title

Number of Participants with Adverse Events ^[1]

End point 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.

End point type

Primary

End point timeframe

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.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: A formal hypothesis was not tested in this study.

End point values	Standard of Care	SOC / Evolocumab	Evolocumab + SOC	Evolocumab + SOC / Evolocumab
Number of subjects analysed	442 ^[2]	374 ^[3]	882 ^[4]	777 ^[5]
Units: participants
All adverse events	327	342	728	718
Adverse events ≥ grade 3	46	111	99	229
Adverse events ≥ grade 4	2	8	11	28
Serious adverse events	30	76	72	172
AEs leading to discontinuation of evolocumab	0	16	28	27
Fatal adverse events	0	1	0	3

Notes
[2] - All randomized participants
[3] - All participants who received evolocumab in the All-IP period
[4] - All randomized participants
[5] - All participants who received evolocumab in the All-IP period

No statistical analyses for this end point

Secondary: Low-density Lipoprotein Cholesterol (LDL-C) Level at Week 24 and Week 52

Top of page

End point title

Low-density Lipoprotein Cholesterol (LDL-C) Level at Week 24 and Week 52

End point description

End point type

Secondary

End point timeframe

Baseline of the parent study and extension study weeks 24 and 52

End point values	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
Number of subjects analysed	442	882	120	239	322	643
Units: mg/dL
arithmetic mean (standard deviation)
Parent Study Baseline	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 (n = 416, 852, 113, 232, 303, 620)	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 (n = 399, 826, 113, 224, 286, 602)	140.5 ( 40.0 )	65.0 ( 34.4 )	143.1 ( 39.8 )	64.1 ( 33.2 )	139.4 ( 40.1 )	65.3 ( 34.9 )

No statistical analyses for this end point

Secondary: Non-high-density Lipoprotein Cholesterol (non-HDL-C) Level at Week 24 and Week 52

Top of page

End point title

Non-high-density Lipoprotein Cholesterol (non-HDL-C) Level at Week 24 and Week 52

End point description

End point type

Secondary

End point timeframe

Baseline of the parent study and extension study weeks 24 and 52

End point values	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
Number of subjects analysed	442	882	120	239	322	643
Units: mg/dL
arithmetic mean (standard deviation)
Parent Study Baseline	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 (n = 416, 852, 113, 232, 303, 620)	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 (n = 399, 825, 113, 224, 286, 601)	164.9 ( 44.5 )	85.3 ( 39.0 )	168.8 ( 45.3 )	85.0 ( 38.4 )	163.4 ( 44.1 )	85.4 ( 39.2 )

No statistical analyses for this end point

Secondary: Apolipoprotein B Level at Week 24 and Week 52

Top of page

End point title

Apolipoprotein B Level at Week 24 and Week 52

End point description

End point type

Secondary

End point timeframe

Baseline of the parent study and extension study weeks 24 and 52

End point values	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
Number of subjects analysed	442	882	120	239	322	643
Units: mg/dL
arithmetic mean (standard deviation)
Parent Study Baseline	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 (n = 416, 852, 113, 232, 303, 620)	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 (401, 834, 113, 227, 288, 607)	109.5 ( 26.8 )	61.6 ( 23.5 )	110.7 ( 26.3 )	61.7 ( 23.0 )	109.1 ( 27.0 )	61.6 ( 23.7 )

No statistical analyses for this end point

Secondary: Total Cholesterol/HDL-C Ratio at Week 24 and Week 52

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End point title

Total Cholesterol/HDL-C Ratio at Week 24 and Week 52

End point description

End point type

Secondary

End point timeframe

Baseline of the parent study and extension study weeks 24 and 52

End point values	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
Number of subjects analysed	442	882	120	239	322	643
Units: ratio
arithmetic mean (standard deviation)
Parent Study Baseline	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 (n = 416, 852, 113, 232, 303, 620)	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 (n = 399, 825, 113, 224, 286, 601)	4.277 ( 1.652 )	2.626 ( 1.025 )	4.252 ( 1.434 )	2.622 ( 1.033 )	4.286 ( 1.733 )	2.628 ( 1.023 )

No statistical analyses for this end point

Secondary: Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24 and Week 52

Top of page

End point title

Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24 and Week 52

End point description

End point type

Secondary

End point timeframe

Baseline of the parent study and extension study weeks 24 and 52

End point values	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
Number of subjects analysed	442	882	120	239	322	643
Units: ratio
arithmetic mean (standard deviation)
Parent Study Baseline	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 (n = 416, 852, 113, 232, 303, 620)	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 (n = 401, 834, 113, 227, 288, 607)	0.726 ( 0.256 )	0.394 ( 0.185 )	0.719 ( 0.216 )	0.393 ( 0.186 )	0.729 ( 0.271 )	0.394 ( 0.185 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

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 additional 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).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

SOC-controlled Period: SOC

Reporting group description

Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period).

Reporting group title

SOC-controlled Period: Evolocumab + SOC

Reporting group description

Participants received evolocumab 420 mg once a month for the first year of the study (SOC-controlled period).

Reporting group title

All-IP Period: SOC / Evolocumab

Reporting group description

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

Reporting group title

All-IP Period: Evolocumab + SoC / Evolocumab

Reporting group description

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

Reporting group title

All-IP Period: Total

Reporting group description

All participants in the All-IP period who received evolocumab 420 mg QM for up to 4 years.

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
Total subjects affected by serious adverse events
subjects affected / exposed	30 / 442 (6.79%)	72 / 882 (8.16%)	78 / 398 (19.60%)	181 / 822 (22.02%)	259 / 1220 (21.23%)
number of deaths (all causes)	2	1	3	13	16
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma gastric
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenoma benign
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal squamous cell carcinoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
B-cell lymphoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	2 / 398 (0.50%)	1 / 822 (0.12%)	3 / 1220 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign neoplasm of bladder
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	1 / 398 (0.25%)	5 / 822 (0.61%)	6 / 1220 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 5	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangiocarcinoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	2 / 398 (0.50%)	1 / 822 (0.12%)	3 / 1220 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hairy cell leukaemia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cancer metastatic
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Intraductal papilloma of breast
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intraductal proliferative breast lesion
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Kaposi's sarcoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Lung neoplasm malignant
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mantle cell lymphoma stage IV
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lymph nodes
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myxoid liposarcoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
Papillary thyroid cancer
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	2 / 398 (0.50%)	4 / 822 (0.49%)	6 / 1220 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 2	2 / 5	3 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal adenoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small cell lung cancer
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small cell lung cancer metastatic
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid adenoma
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine cancer
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Accelerated hypertension
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 3	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Cholecystectomy
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Knee arthroplasty
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Medical device removal
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ectopic pregnancy
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 442 (0.23%)	4 / 882 (0.45%)	1 / 398 (0.25%)	6 / 822 (0.73%)	7 / 1220 (0.57%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 1	0 / 6	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypothermia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mass
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nodule
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 442 (0.23%)	4 / 882 (0.45%)	0 / 398 (0.00%)	7 / 822 (0.85%)	7 / 1220 (0.57%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0	0 / 8	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Organ failure
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Contrast media allergy
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 442 (0.00%)	2 / 882 (0.23%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystocele
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Menorrhagia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postmenopausal haemorrhage
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	4 / 822 (0.49%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 6	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	2 / 398 (0.50%)	2 / 822 (0.24%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal polyp
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngeal oedema
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 442 (0.45%)	1 / 882 (0.11%)	1 / 398 (0.25%)	4 / 822 (0.49%)	5 / 1220 (0.41%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	1 / 5	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary granuloma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus polyp
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord polyp
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Alcohol abuse
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alcohol withdrawal syndrome
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anxiety
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hallucination
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Electrocardiogram ST segment abnormal
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HIV test positive
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Heart rate increased
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Anaesthetic complication
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac contusion
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	2 / 398 (0.50%)	2 / 822 (0.24%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	2 / 398 (0.50%)	0 / 822 (0.00%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc injury
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 442 (0.00%)	2 / 882 (0.23%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle rupture
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haematuria
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural complication
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural nausea
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural vomiting
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary contusion
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	2 / 398 (0.50%)	1 / 822 (0.12%)	3 / 1220 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Scapula fracture
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon injury
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention postoperative
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	3 / 822 (0.36%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	2 / 442 (0.45%)	4 / 882 (0.45%)	1 / 398 (0.25%)	9 / 822 (1.09%)	10 / 1220 (0.82%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 1	0 / 9	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve disease
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve disease mixed
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve incompetence
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve sclerosis
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 442 (0.23%)	1 / 882 (0.11%)	2 / 398 (0.50%)	7 / 822 (0.85%)	9 / 1220 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	1 / 9	1 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial thrombosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	2 / 398 (0.50%)	4 / 822 (0.49%)	6 / 1220 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery embolism
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	2 / 822 (0.24%)	3 / 1220 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve disease
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve disease mixed
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nodal rhythm
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain stem haemorrhage
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral thrombosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical radiculopathy
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	2 / 398 (0.50%)	0 / 822 (0.00%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness postural
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Motor neurone disease
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myelopathy
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 442 (0.00%)	2 / 882 (0.23%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal claudication
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 442 (0.00%)	2 / 882 (0.23%)	0 / 398 (0.00%)	4 / 822 (0.49%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tension headache
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Trigeminal neuralgia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertebrobasilar insufficiency
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Sudden hearing loss
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo positional
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	2 / 398 (0.50%)	2 / 822 (0.24%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cataract cortical
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Corneal defect
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eyelid ptosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Keratitis
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brunner's gland hyperplasia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Faeces discoloured
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	2 / 398 (0.50%)	0 / 822 (0.00%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	2 / 822 (0.24%)	3 / 1220 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar hernia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive pancreatitis
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal spasm
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal haematoma
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenic artery aneurysm
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tooth impacted
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Biliary dyskinesia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	2 / 398 (0.50%)	1 / 822 (0.12%)	3 / 1220 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	4 / 822 (0.49%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	4 / 822 (0.49%)	5 / 1220 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 5	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 442 (0.23%)	1 / 882 (0.11%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder prolapse
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Calculus bladder
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	3 / 822 (0.36%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Thyroid mass
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroiditis acute
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	3 / 822 (0.36%)	3 / 1220 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	3 / 822 (0.36%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chondrocalcinosis pyrophosphate
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chondropathy
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Costochondritis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	2 / 398 (0.50%)	1 / 822 (0.12%)	3 / 1220 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dupuytren's contracture
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc disorder
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	2 / 398 (0.50%)	0 / 822 (0.00%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 442 (0.23%)	3 / 882 (0.34%)	5 / 398 (1.26%)	9 / 822 (1.09%)	14 / 1220 (1.15%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 5	0 / 11	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoporosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	3 / 822 (0.36%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Synovial cyst
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendonitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendiceal abscess
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 442 (0.23%)	5 / 882 (0.57%)	2 / 398 (0.50%)	3 / 822 (0.36%)	5 / 1220 (0.41%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 2	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial pyelonephritis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	2 / 398 (0.50%)	2 / 822 (0.24%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis infective
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis staphylococcal
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridial infection
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	1 / 822 (0.12%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 442 (0.23%)	0 / 882 (0.00%)	0 / 398 (0.00%)	2 / 822 (0.24%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis bacterial
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infective spondylitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint abscess
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ophthalmic herpes simplex
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 442 (0.00%)	3 / 882 (0.34%)	2 / 398 (0.50%)	4 / 822 (0.49%)	6 / 1220 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2	0 / 6	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	1 / 398 (0.25%)	3 / 822 (0.36%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rocky mountain spotted fever
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal sepsis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	4 / 822 (0.49%)	4 / 1220 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 442 (0.00%)	3 / 882 (0.34%)	2 / 398 (0.50%)	0 / 822 (0.00%)	2 / 1220 (0.16%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	1 / 398 (0.25%)	0 / 822 (0.00%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 442 (0.00%)	1 / 882 (0.11%)	0 / 398 (0.00%)	0 / 822 (0.00%)	0 / 1220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 442 (0.00%)	0 / 882 (0.00%)	0 / 398 (0.00%)	1 / 822 (0.12%)	1 / 1220 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-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
Total subjects affected by non serious adverse events
subjects affected / exposed	217 / 442 (49.10%)	513 / 882 (58.16%)	311 / 398 (78.14%)	626 / 822 (76.16%)	937 / 1220 (76.80%)
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	10 / 442 (2.26%)	15 / 882 (1.70%)	25 / 398 (6.28%)	35 / 822 (4.26%)	60 / 1220 (4.92%)
occurrences all number	11	16	31	47	78
Procedural pain
subjects affected / exposed	4 / 442 (0.90%)	4 / 882 (0.45%)	20 / 398 (5.03%)	23 / 822 (2.80%)	43 / 1220 (3.52%)
occurrences all number	5	4	27	26	53
Vascular disorders
Hypertension
subjects affected / exposed	20 / 442 (4.52%)	52 / 882 (5.90%)	40 / 398 (10.05%)	99 / 822 (12.04%)	139 / 1220 (11.39%)
occurrences all number	21	60	51	113	164
Nervous system disorders
Dizziness
subjects affected / exposed	12 / 442 (2.71%)	18 / 882 (2.04%)	20 / 398 (5.03%)	51 / 822 (6.20%)	71 / 1220 (5.82%)
occurrences all number	12	21	21	61	82
Headache
subjects affected / exposed	12 / 442 (2.71%)	54 / 882 (6.12%)	28 / 398 (7.04%)	44 / 822 (5.35%)	72 / 1220 (5.90%)
occurrences all number	12	72	36	61	97
General disorders and administration site conditions
Fatigue
subjects affected / exposed	5 / 442 (1.13%)	31 / 882 (3.51%)	16 / 398 (4.02%)	43 / 822 (5.23%)	59 / 1220 (4.84%)
occurrences all number	5	38	17	61	78
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	11 / 442 (2.49%)	41 / 882 (4.65%)	33 / 398 (8.29%)	61 / 822 (7.42%)	94 / 1220 (7.70%)
occurrences all number	12	43	38	82	120
Gastrooesophageal reflux disease
subjects affected / exposed	13 / 442 (2.94%)	23 / 882 (2.61%)	20 / 398 (5.03%)	32 / 822 (3.89%)	52 / 1220 (4.26%)
occurrences all number	14	23	23	33	56
Nausea
subjects affected / exposed	4 / 442 (0.90%)	23 / 882 (2.61%)	23 / 398 (5.78%)	32 / 822 (3.89%)	55 / 1220 (4.51%)
occurrences all number	4	33	28	40	68
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	19 / 442 (4.30%)	41 / 882 (4.65%)	40 / 398 (10.05%)	77 / 822 (9.37%)	117 / 1220 (9.59%)
occurrences all number	21	43	63	106	169
Oropharyngeal pain
subjects affected / exposed	10 / 442 (2.26%)	24 / 882 (2.72%)	14 / 398 (3.52%)	42 / 822 (5.11%)	56 / 1220 (4.59%)
occurrences all number	11	24	16	47	63
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	18 / 442 (4.07%)	59 / 882 (6.69%)	63 / 398 (15.83%)	109 / 822 (13.26%)	172 / 1220 (14.10%)
occurrences all number	25	70	87	142	229
Back pain
subjects affected / exposed	22 / 442 (4.98%)	62 / 882 (7.03%)	51 / 398 (12.81%)	117 / 822 (14.23%)	168 / 1220 (13.77%)
occurrences all number	23	68	67	152	219
Muscle spasms
subjects affected / exposed	10 / 442 (2.26%)	25 / 882 (2.83%)	21 / 398 (5.28%)	39 / 822 (4.74%)	60 / 1220 (4.92%)
occurrences all number	13	27	24	48	72
Musculoskeletal pain
subjects affected / exposed	12 / 442 (2.71%)	28 / 882 (3.17%)	19 / 398 (4.77%)	62 / 822 (7.54%)	81 / 1220 (6.64%)
occurrences all number	14	29	22	72	94
Osteoarthritis
subjects affected / exposed	4 / 442 (0.90%)	22 / 882 (2.49%)	27 / 398 (6.78%)	54 / 822 (6.57%)	81 / 1220 (6.64%)
occurrences all number	4	23	35	67	102
Pain in extremity
subjects affected / exposed	14 / 442 (3.17%)	44 / 882 (4.99%)	32 / 398 (8.04%)	70 / 822 (8.52%)	102 / 1220 (8.36%)
occurrences all number	16	50	38	84	122
Infections and infestations
Bronchitis
subjects affected / exposed	17 / 442 (3.85%)	48 / 882 (5.44%)	40 / 398 (10.05%)	94 / 822 (11.44%)	134 / 1220 (10.98%)
occurrences all number	19	59	57	135	192
Cystitis
subjects affected / exposed	9 / 442 (2.04%)	15 / 882 (1.70%)	25 / 398 (6.28%)	39 / 822 (4.74%)	64 / 1220 (5.25%)
occurrences all number	11	19	37	61	98
Influenza
subjects affected / exposed	24 / 442 (5.43%)	57 / 882 (6.46%)	47 / 398 (11.81%)	81 / 822 (9.85%)	128 / 1220 (10.49%)
occurrences all number	27	65	60	106	166
Nasopharyngitis
subjects affected / exposed	64 / 442 (14.48%)	148 / 882 (16.78%)	122 / 398 (30.65%)	236 / 822 (28.71%)	358 / 1220 (29.34%)
occurrences all number	84	203	258	471	729
Sinusitis
subjects affected / exposed	15 / 442 (3.39%)	32 / 882 (3.63%)	31 / 398 (7.79%)	68 / 822 (8.27%)	99 / 1220 (8.11%)
occurrences all number	22	37	54	113	167
Upper respiratory tract infection
subjects affected / exposed	29 / 442 (6.56%)	72 / 882 (8.16%)	57 / 398 (14.32%)	118 / 822 (14.36%)	175 / 1220 (14.34%)
occurrences all number	35	85	86	160	246

More information

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Were there any global substantial amendments to the protocol? Yes

15 Aug 2011

- added "OSLER" study name - added a standard of care control group - clarified that subjects should remain in follow-up after discontinuation of investigational product and updated the list of possible reasons for withdrawal from investigational product - added an exploratory objective of estimation of cardiovascular event rates - added international units for lipid concentrations for informational purposes - opened inclusion criteria to include all qualifying evolocumab parent protocols - clarified measurement methods for LDL-C by preparative ultracentrifugation and by calculation (added a footnote to the schedule of assessments) - revised Section 8.1 of the protocol (Removal of Subjects) in accordance with current regulatory guidelines - clarified that death and certain cardiovascular events that were submitted for adjudication were not submitted as adverse event/serious adverse events until the event was adjudicated negatively (did not qualify as adjudicated endpoint) - added adjudicated events as exploratory endpoints - added a week 4 study visit - decreased the study duration to 1 year - added description of randomization (Section 5.1 of the protocol) - updated the statistical section to reflect the control group

08 Sep 2011

- clarified measurement methods for LDL-C by a preparative ultracentrifugation and by calculation (added new section [Section 7.1.2.3 of the protocol] for lipid measurements) - added fasting vitamin E measurements to the protocol - removed the term "treatment emergent" from the adverse event section of the protocol

24 Apr 2012

- updated the evolocumab background section with the most currently available data - incorporated new adverse event/serious adverse event language - increased the sample size from approximately 375 to 1600 - increased the number of study centers from 200 to 240 - increased the study duration from 1 year to 5 years or until evolocumab becomes commercially available - aligned the parent end of study/ extension day 1 assessments for Q2W subjects from parent studies 20101154 (monotherapy) and 20101155 (combination therapy) - added additional language to help highlight the importance of maintaining the blind during the first 12 weeks of the study - added steroid testing (ACTH, FSH, LH, cortisol, testosterone, estradiol) measurements to the protocol removed the term "absolute" from all endpoints

20 Jun 2012

- changed the study duration language to approximately 5 years (or until the investigator's recommendation of discontinuation, Amgen's recommendation of discontinuation, the subjects' decision to discontinue for any reason, or until an administrative decision is made to close the study) per global regulatory feedback - highlighted that week 4 visit was required for all subjects - added a steroid substudy rather than requiring all subjects to undergo steroid sampling - clarified pregnancy and lactation reporting requirements decreased the frequency of anti-evolocumab antibody collection after year 1

26 Feb 2014

- updated safety reporting language to include device reporting - added new evolocumab formulation and AI/pen language - introduced the simplified terminology of monthly dosing - clarified blinding requirements for laboratory test results - updated the statistical analyses in Protocol Amendment 5 (Section 16.1.1) to reflect the final study analysis.

09 Mar 2015

- removed the external DMC after the DMC's expressed preference to not review open-label, uncontrolled safety data. Safety monitoring continued to be performed by AMGEN. - remove non-coronary revascularizations from adjudication. Collection and review of such events is achieved by specific eCRF and safety review by Amgen Global Patient Safety.

12 Nov 2015

- updated safety language, ie, addition of adverse device effects collection - updated end of study language, ie, after the first year, quarterly visits will continue up to week 260 (approximately 5 years) - updated pregnancy and lactation reporting and pregnancy and lactation notification worksheets.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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