Download PDF

Clinical Trial Results:
AspECT - A phase III, randomised study of aspirin and esomeprazole chemoprevention in Barrett's metaplasia & oesophagitis.

Summary
EudraCT number	2004-003836-77
Trial protocol	GB
Global end of trial date	10 Aug 2017

Results information
Results version number	v1(current)
This version publication date	26 Aug 2018
First version publication date	26 Aug 2018
Other versions
Summary report(s)	AspECT_PrimaryPublication_Lancet_04Aug2018

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

OCTO-003

ISRCTN number

ISRCTN85156844

US NCT number

NCT00357682

WHO universal trial number (UTN)

Sponsor organisation name

University of Oxford

Sponsor organisation address

Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom, OX4 2PG

Public contact

AspECT Trial Office, Oncology Clinical Trials Unit, University of Oxford, +44 1865 617331, enquiries@oncology.ox.ac.uk

Scientific contact

AspECT Trial Office, Oncology Clinical Trials Unit, University of Oxford, +44 1865 617331, enquiries@oncology.ox.ac.uk

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

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

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

Analysis stage

Final

Date of interim/final analysis

31 May 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 May 2017

Global end of trial reached?

Yes

Global end of trial date

10 Aug 2017

Was the trial ended prematurely?

Main objective of the trial

To assess whether intervention with aspirin results in a decreased all causes of mortality or conversion rate from Barrett’s metaplasia to adenocarcinoma or high grade dysplasia. To assess whether high dose PPI therapy decreases the all causes of mortality or conversion rate from Barrett’s Metaplasia to adenocarcinoma or high grade dysplasia.

Protection of trial subjects

A data safety monitoring committee was established to review the data at regular intervals and ensure the safety of the trial patients. Patient information sheets were provided to subjects prior to randomisation. Nurses and consultants also detailed to the patients the option to withdraw from the trial treatment and follow up at any point throughout the trial. Patients were also provided with contact details of the clinical trial office and were encouraged to reach out if they had any questions at any time. All adverse events throughout the trial were reported immediately to the trial office and reviewed if deemed serious.

Background therapy

Proton Pump Inhibitors (PPI) are used in to reduce acid in patients experiencing reflux from the stomach. Aspirin is a drug mainly used to treat pain, fever, or inflammation.

Evidence for comparator

It has yet to be determined whether high or low dose PPI is optimal in treating acid reflux and potentially reducing oesophegeal cancer. Long term daily use of aspirin has been seen to reduce the risk of a number of cancers, most notably colon cancer. It is yet unknown for sure if this is the case in oesophegeal cancer.

Actual start date of recruitment

04 Mar 2005

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Ethical reason, Regulatory reason, Scientific research, Safety

Long term follow-up duration

10 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 2491

Country: Number of subjects enrolled

Canada: 44

Worldwide total number of subjects

2535

EEA total number of subjects

2491

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1836

From 65 to 84 years

693

85 years and over

Subject disposition

Top of page

Recruitment details

Eligible participants were recruited from 4th March 2005 to 25th February 2009 in 86 centres in the United Kingdom and 1 centre in Canada. Participants were recruited by gastroenterologists and upper gastrointestinal surgeons at hospitals through clinics and endoscopy lists, including new and existing BE diagnoses.

Screening details

At least 5,726 patients were screened in 87 sites. Of the 5,726 screening records, 2,582 (2083 not meeting exclusion and 499 other reasons) were excluded based on trial exclusion reasons (contraindication to study drug, outside age range etc). Of the 3,100 remaining, 587 declined participation in the trial, leaving 2,557 total patients randomised

Period 1 title

Randomisation (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

No blinding was performed

Are arms mutually exclusive

Yes

Arm A

Arm description

Low Dose PPI (20mg daily)

Arm type

Active comparator

Investigational medicinal product name

Esomeprazole

Investigational medicinal product code

D9612000000

Other name

Nexium

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

20mg/day

Arm B

Arm description

High Dose PPI (80mg daily)

Arm type

Active comparator

Investigational medicinal product name

Esomeprazole

Investigational medicinal product code

D9612000000

Other name

Nexium

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

40mg/twice daily

Arm C

Arm description

Low Dose PPI (20mg daily) & Aspirin (300mg daily)

Arm type

Active comparator

Investigational medicinal product name

Esomeprazole

Investigational medicinal product code

D9612000000

Other name

Nexium

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

20mg/day

Investigational medicinal product name

Aspirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300mg/day

Arm D

Arm description

High Dose PPI (80mg daily) & Aspirin (300mg daily)

Arm type

Active comparator

Investigational medicinal product name

Esomeprazole

Investigational medicinal product code

D9612000000

Other name

Nexium

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

40mg/twice daily

Investigational medicinal product name

Aspirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300mg/day

Number of subjects in period 1	Arm A	Arm B	Arm C	Arm D
Started	699	698	566	572
Completed	699	698	566	572

Baseline characteristics

Top of page

Reporting group title

Arm A

Reporting group description

Low Dose PPI (20mg daily)

Reporting group title

Arm B

Reporting group description

High Dose PPI (80mg daily)

Reporting group title

Arm C

Reporting group description

Low Dose PPI (20mg daily) & Aspirin (300mg daily)

Reporting group title

Arm D

Reporting group description

High Dose PPI (80mg daily) & Aspirin (300mg daily)

Reporting group values	Arm A	Arm B	Arm C	Arm D	Total
Number of subjects	699	698	566	572	2535
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	495	494	429	418	1836
From 65-84 years	202	204	134	153	693
85 years and over	2	0	3	1	6
Age continuous
Continuous age statistics by treatment arm and primary trial comparisons
Units: years
median (inter-quartile range (Q1-Q3))	59 (51 to 65)	59 (51 to 66)	58 (50 to 64)	58 (50 to 65)	-
Gender categorical
Gender characteristics by treatment arm and primary trial comparisons
Units: Subjects
Female	135	136	118	124	513
Male	564	562	448	448	2022

Subject analysis set title

Aspirin

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients randomised to receive 300mg daily aspirin

Subject analysis set title

No Aspirin

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects randomised to receive no aspirin

Subject analysis set title

Low Dose PPI

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects randomised to receive 20mg daily PPI

Subject analysis set title

High Dose PPI

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects randomised to receive 80mg PPI daily

Subject analysis sets values	Aspirin	No Aspirin	Low Dose PPI	High Dose PPI
Number of subjects	1138	1142	1265	1270
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	847	854	924	912
From 65-84 years	287	287	336	357
85 years and over	4	1	5	1
Age continuous
Continuous age statistics by treatment arm and primary trial comparisons
Units: years
median (inter-quartile range (Q1-Q3))	58 (50 to 65)	58 (50 to 65)	59 (51 to 65)	59 (51 to 65)
Gender categorical
Gender characteristics by treatment arm and primary trial comparisons
Units: Subjects
Female	242	242	253	260
Male	896	900	1012	1010

End points

Top of page

Reporting group title

Arm A

Reporting group description

Low Dose PPI (20mg daily)

Reporting group title

Arm B

Reporting group description

High Dose PPI (80mg daily)

Reporting group title

Arm C

Reporting group description

Low Dose PPI (20mg daily) & Aspirin (300mg daily)

Reporting group title

Arm D

Reporting group description

High Dose PPI (80mg daily) & Aspirin (300mg daily)

Subject analysis set title

Aspirin

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients randomised to receive 300mg daily aspirin

Subject analysis set title

No Aspirin

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects randomised to receive no aspirin

Subject analysis set title

Low Dose PPI

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects randomised to receive 20mg daily PPI

Subject analysis set title

High Dose PPI

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects randomised to receive 80mg PPI daily

Primary: First event of death, oesophegeal adenocarcinoma, high grade dysplasia

Top of page

End point title

First event of death, oesophegeal adenocarcinoma, high grade dysplasia

End point description

Death is recorded on a continuous basis through reporting from trial sites. Oesophegeal adenocarcinoma is recorded through endoscopies taken every two years or ad-hoc at clinician decision High Grade Dysplasia is recorded through endoscopies taken every two years or ad-hoc at clinician decision

End point type

Primary

End point timeframe

Events are assessed from the date of randomisation to the end of study which can be patient withdrawal, loss to follow up or study end (8 years or 10 years from randomisation, depending on consent)

End point values	Arm A	Arm B	Arm C	Arm D	Aspirin	No Aspirin	Low Dose PPI	High Dose PPI
Number of subjects analysed	699	698	566	572	1138	1142	1265	1270
Units: 20	99	87	75	52	127	154	174	139

Primary Analysis (PPI)

Statistical analysis description

Accelerated Failure Time (AFT) analysis comparing time to primary event in low dose PPI (20mg) patients to high dose PPI (80mg) patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and aspirin randomisation group.

Comparison groups

Low Dose PPI v High Dose PPI

Number of subjects included in analysis

2535

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.068

Method

Accelerated Failure Time

Parameter type

Time Ratio

Point estimate

1.24

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

1.57

Notes
[1] - 5% significance level is considered statistically significant

Primary Analysis (Aspirin)

Statistical analysis description

Accelerated Failure Time (AFT) analysis comparing time to primary event in aspirin patients to non-aspirin patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and PPI randomisation group.

Comparison groups

No Aspirin v Aspirin

Number of subjects included in analysis

2280

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.037

Method

Accelerated Failure Time

Parameter type

Time Ratio

Point estimate

1.27

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

1.58

Secondary Analysis (PPI All cause mortality)

Statistical analysis description

Accelerated Failure Time (AFT) analysis comparing time to all cause mortality in low dose PPI (20mg) patients to high dose PPI (80mg) patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and aspirin randomisation group.

Comparison groups

Low Dose PPI v High Dose PPI

Number of subjects included in analysis

2535

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.039

Method

Accelerated Failure Time

Parameter type

Time Ratio

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

1.82

Secondary Analysis (PPI Oesophegeal Adenocarcinoma

Statistical analysis description

Accelerated Failure Time (AFT) analysis comparing time to oesophegeal adenocarcinoma in low dose PPI (20mg) patients to high dose PPI (80mg) patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and aspirin randomisation group.

Comparison groups

Low Dose PPI v High Dose PPI

Number of subjects included in analysis

2535

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.864

Method

Accelerated Failure Time

Parameter type

Time Ratio

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.61

Secondary Analysis (High Grade Dysplasia)

Statistical analysis description

Accelerated Failure Time (AFT) analysis comparing time to high grade dysplasia in low dose PPI (20mg) patients to high dose PPI (80mg) patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and aspirin randomisation group.

Comparison groups

Low Dose PPI v High Dose PPI

Number of subjects included in analysis

2535

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.119

Method

Accelerated Failure Time

Parameter type

Time Ratio

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

2.02

Secondary Analysis (Aspirin All Cause Mortality)

Statistical analysis description

Accelerated Failure Time (AFT) analysis comparing time to all cause mortality in aspirin patients to non-aspirin patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and PPI randomisation group.

Comparison groups

Aspirin v No Aspirin

Number of subjects included in analysis

2280

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.159

Method

Accelerated Failure Time

Parameter type

Time Ratio

Point estimate

1.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

1.7

Secondary Analysis (Aspirin and oesophegeal adeno)

Statistical analysis description

Accelerated Failure Time (AFT) analysis comparing time to oesophegeal adenocarcinoma in aspirin patients to non-aspirin patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and PPI randomisation group.

Comparison groups

Aspirin v No Aspirin

Number of subjects included in analysis

2280

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.921

Method

Accelerated Failure Time

Parameter type

Time Ratio

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

1.64

Secondary Analysis (Aspirin High Grade Dysplasia)

Statistical analysis description

Accelerated Failure Time (AFT) analysis comparing time to high grade dysplasia in aspirin patients to non-aspirin patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and PPI randomisation group.

Comparison groups

Aspirin v No Aspirin

Number of subjects included in analysis

2280

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.053

Method

Accelerated Failure Time

Parameter type

Time Ratio

Point estimate

1.51

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

2.29

Secondary Analysis (PPI Cause Specific Mortality)

Statistical analysis description

Accelerated Failure Time (AFT) analysis comparing time to cause specific mortality in low dose PPI (20mg) patients to high dose PPI (80mg) patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and aspirin randomisation group. Cause Specific Mortality: Death due to oesophegeal adenocarcinoma

Comparison groups

Low Dose PPI v High Dose PPI

Number of subjects included in analysis

2535

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.336

Method

Accelerated Failure Time

Parameter type

Time Ratio

Point estimate

1.55

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

3.8

Secondary Analysis (Aspirin Cause Specific Death)

Statistical analysis description

Accelerated Failure Time (AFT) analysis comparing time to cause specific mortality in aspirin patients to non-aspirin patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and PPI randomisation group.

Comparison groups

Aspirin v No Aspirin

Number of subjects included in analysis

2280

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.983

Method

Accelerated Failure Time

Parameter type

Time Ratio

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.38

upper limit

2.69

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events were reported from the date of randomisation until 30 days after the end of treatment

Adverse event reporting additional description

Adverse events were reported to the trial team by sites as soon as possible after the events occurred.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Arm A

Reporting group description

Low Dose PPI (20mg daily)

Reporting group title

Arm B

Reporting group description

High Dose PPI (80mg daily)

Reporting group title

Arm C

Reporting group description

Low Dose PPI (20mg daily) & Aspirin (300mg daily)

Reporting group title

Arm D

Reporting group description

High Dose PPI (80mg daily) & Aspirin (300mg daily)

Reporting group title

Aspirin

Reporting group description

Patients randomised to 300mg daily aspirin treatment

Reporting group title

No Aspirin

Reporting group description

Patients randomised to received no aspirin treatment

Reporting group title

Low Dose PPI

Reporting group description

Patients randomised to 20mg daily PPI treatment

Reporting group title

High Dose PPI

Reporting group description

Patients randomised to 80mg daily PPI treatment

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: The reason is that adverse events (non-serious) were only recorded if the event led to the patient withdrawing from study medication. Non serious AE details were not recorded.

Serious adverse events	Arm A	Arm B	Arm C	Arm D	Aspirin	No Aspirin	Low Dose PPI	High Dose PPI
Total subjects affected by serious adverse events
subjects affected / exposed	183 / 699 (26.18%)	195 / 698 (27.94%)	176 / 566 (31.10%)	164 / 572 (28.67%)	340 / 1138 (29.88%)	378 / 1142 (33.10%)	359 / 1265 (28.38%)	359 / 1270 (28.27%)
number of deaths (all causes)	48	42	46	27	73	90	94	69
number of deaths resulting from adverse events	39	33	30	17	47	72	69	50
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bile duct cancer
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
Bladder Cancer
subjects affected / exposed	1 / 699 (0.14%)	2 / 698 (0.29%)	0 / 566 (0.00%)	2 / 572 (0.35%)	2 / 1138 (0.18%)	3 / 1142 (0.26%)	1 / 1265 (0.08%)	4 / 1270 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 2	0 / 2	0 / 4	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
Brain cancer
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Breast cancer
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 3	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 3	0 / 2	0 / 1
Colorectal cancer
subjects affected / exposed	6 / 699 (0.86%)	4 / 698 (0.57%)	2 / 566 (0.35%)	4 / 572 (0.70%)	6 / 1138 (0.53%)	10 / 1142 (0.88%)	8 / 1265 (0.63%)	8 / 1270 (0.63%)
occurrences causally related to treatment / all	0 / 7	0 / 5	0 / 2	0 / 4	0 / 6	0 / 12	0 / 9	0 / 9
deaths causally related to treatment / all	0 / 4	0 / 1	0 / 2	0 / 1	0 / 3	0 / 5	0 / 6	0 / 2
Endometrial cancer
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder cancer
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
Gastric - Adenocarcinoma
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Laryngeal - Squamous cell carcinoma
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukemia
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
Liposarcoma
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Lung cancer
subjects affected / exposed	5 / 699 (0.72%)	7 / 698 (1.00%)	7 / 566 (1.24%)	3 / 572 (0.52%)	10 / 1138 (0.88%)	12 / 1142 (1.05%)	12 / 1265 (0.95%)	10 / 1270 (0.79%)
occurrences causally related to treatment / all	0 / 5	0 / 7	0 / 8	0 / 5	0 / 13	0 / 12	0 / 13	0 / 12
deaths causally related to treatment / all	0 / 4	0 / 5	0 / 7	0 / 2	0 / 9	0 / 9	0 / 11	0 / 7
Lymphoma
subjects affected / exposed	2 / 699 (0.29%)	1 / 698 (0.14%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	3 / 1142 (0.26%)	3 / 1265 (0.24%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 1	0 / 2	0 / 3	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1	0 / 2	0 / 2	0 / 3	0 / 1
Mesothelioma
subjects affected / exposed	1 / 699 (0.14%)	2 / 698 (0.29%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	3 / 1142 (0.26%)	1 / 1265 (0.08%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 3	0 / 1	0 / 2
Metastatic cancer unknown origin
subjects affected / exposed	0 / 699 (0.00%)	2 / 698 (0.29%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 1	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 1	0 / 2	0 / 1	0 / 2
Myeloma
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
Neuroendocrine tumour
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	2 / 566 (0.35%)	0 / 572 (0.00%)	2 / 1138 (0.18%)	1 / 1142 (0.09%)	3 / 1265 (0.24%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 2	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal cancer
subjects affected / exposed	3 / 699 (0.43%)	1 / 698 (0.14%)	2 / 566 (0.35%)	0 / 572 (0.00%)	2 / 1138 (0.18%)	4 / 1142 (0.35%)	5 / 1265 (0.40%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 2	0 / 0	0 / 2	0 / 4	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 1	0 / 2	0 / 0	0 / 2	0 / 4	0 / 5	0 / 1
Oral cancer
subjects affected / exposed	1 / 699 (0.14%)	2 / 698 (0.29%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	3 / 1142 (0.26%)	2 / 1265 (0.16%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 1	0 / 2	0 / 3	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cancer
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic cancer
subjects affected / exposed	1 / 699 (0.14%)	2 / 698 (0.29%)	2 / 566 (0.35%)	0 / 572 (0.00%)	2 / 1138 (0.18%)	3 / 1142 (0.26%)	3 / 1265 (0.24%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2	0 / 0	0 / 2	0 / 4	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0	0 / 1	0 / 3	0 / 2	0 / 2
Prostate cancer
subjects affected / exposed	4 / 699 (0.57%)	7 / 698 (1.00%)	3 / 566 (0.53%)	6 / 572 (1.05%)	8 / 1138 (0.70%)	11 / 1142 (0.96%)	6 / 1265 (0.47%)	13 / 1270 (1.02%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 3	0 / 6	0 / 9	0 / 11	0 / 7	0 / 13
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Renal cancer
subjects affected / exposed	3 / 699 (0.43%)	1 / 698 (0.14%)	2 / 566 (0.35%)	1 / 572 (0.17%)	3 / 1138 (0.26%)	4 / 1142 (0.35%)	5 / 1265 (0.40%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 2	0 / 1	0 / 3	0 / 4	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 1	0 / 2	0 / 3	0 / 0
Skin cancer melanoma
subjects affected / exposed	0 / 699 (0.00%)	2 / 698 (0.29%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	0 / 1265 (0.00%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
Skin cancer non-melanoma
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	2 / 1142 (0.18%)	3 / 1265 (0.24%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1	0 / 2	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Testicular cancer
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hematoma
subjects affected / exposed	0 / 699 (0.00%)	2 / 698 (0.29%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	0 / 1265 (0.00%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	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	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	2 / 572 (0.35%)	3 / 1138 (0.26%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 3	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ruptured aortic arch aneurism
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 2	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1
Thromboembolic event
subjects affected / exposed	5 / 699 (0.72%)	7 / 698 (1.00%)	6 / 566 (1.06%)	4 / 572 (0.70%)	10 / 1138 (0.88%)	12 / 1142 (1.05%)	11 / 1265 (0.87%)	11 / 1270 (0.87%)
occurrences causally related to treatment / all	0 / 5	0 / 7	0 / 6	0 / 4	0 / 10	0 / 12	0 / 11	0 / 11
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1
Vasculitis
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Fetal death
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fever
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Flu like symptoms
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Injection site reaction
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Localized edema
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	7 / 699 (1.00%)	12 / 698 (1.72%)	7 / 566 (1.24%)	12 / 572 (2.10%)	19 / 1138 (1.67%)	19 / 1142 (1.66%)	14 / 1265 (1.11%)	24 / 1270 (1.89%)
occurrences causally related to treatment / all	0 / 7	0 / 13	0 / 7	0 / 14	0 / 21	0 / 20	0 / 14	0 / 27
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergic reaction
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylaxis
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Autoimmune disorder
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 699 (0.29%)	1 / 698 (0.14%)	3 / 566 (0.53%)	0 / 572 (0.00%)	3 / 1138 (0.26%)	3 / 1142 (0.26%)	5 / 1265 (0.40%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 0	0 / 3	0 / 3	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	9 / 566 (1.59%)	4 / 572 (0.70%)	13 / 1138 (1.14%)	2 / 1142 (0.18%)	11 / 1265 (0.87%)	4 / 1270 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 0	7 / 9	4 / 4	11 / 13	0 / 2	7 / 11	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hiccups
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	3 / 1265 (0.24%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 1	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	1 / 1142 (0.09%)	2 / 1265 (0.16%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 699 (0.00%)	3 / 698 (0.43%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	3 / 1142 (0.26%)	0 / 1265 (0.00%)	4 / 1270 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 1	0 / 1	0 / 3	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tracheal stenosis
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wheezing
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Confusion
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 699 (0.00%)	2 / 698 (0.29%)	0 / 566 (0.00%)	4 / 572 (0.70%)	4 / 1138 (0.35%)	2 / 1142 (0.18%)	0 / 1265 (0.00%)	6 / 1270 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	1 / 4	1 / 4	0 / 2	0 / 0	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mania
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychosis
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 699 (0.00%)	2 / 698 (0.29%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	0 / 1265 (0.00%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 2
Investigations
Blood bilirubin increased
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GGT increased
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vitamin B12 deficiency
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental death
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0
Alcohol abuse
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 2	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
Ankle fracture
subjects affected / exposed	2 / 699 (0.29%)	2 / 698 (0.29%)	3 / 566 (0.53%)	1 / 572 (0.17%)	4 / 1138 (0.35%)	4 / 1142 (0.35%)	5 / 1265 (0.40%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 3	0 / 1	0 / 4	0 / 4	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bruising
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystectomy procedural complication
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 699 (0.14%)	3 / 698 (0.43%)	4 / 566 (0.71%)	3 / 572 (0.52%)	7 / 1138 (0.62%)	4 / 1142 (0.35%)	5 / 1265 (0.40%)	6 / 1270 (0.47%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 4	0 / 4	0 / 8	0 / 5	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
Fracture
subjects affected / exposed	2 / 699 (0.29%)	7 / 698 (1.00%)	7 / 566 (1.24%)	4 / 572 (0.70%)	11 / 1138 (0.97%)	9 / 1142 (0.79%)	9 / 1265 (0.71%)	11 / 1270 (0.87%)
occurrences causally related to treatment / all	0 / 2	0 / 7	0 / 8	0 / 4	0 / 12	0 / 9	0 / 10	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Head injury
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	6 / 699 (0.86%)	4 / 698 (0.57%)	2 / 566 (0.35%)	1 / 572 (0.17%)	3 / 1138 (0.26%)	10 / 1142 (0.88%)	8 / 1265 (0.63%)	5 / 1270 (0.39%)
occurrences causally related to treatment / all	2 / 6	0 / 5	0 / 2	0 / 1	0 / 3	2 / 11	2 / 8	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intraoperative gastrointestinal injury
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	2 / 1265 (0.16%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Postoperative hemorrhage
subjects affected / exposed	0 / 699 (0.00%)	2 / 698 (0.29%)	3 / 566 (0.53%)	0 / 572 (0.00%)	3 / 1138 (0.26%)	2 / 1142 (0.18%)	3 / 1265 (0.24%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3	0 / 0	0 / 3	0 / 2	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
Ruptured spleen
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound complication
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	2 / 699 (0.29%)	2 / 698 (0.29%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	4 / 1142 (0.35%)	3 / 1265 (0.24%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1	0 / 0	0 / 1	0 / 4	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	2 / 699 (0.29%)	4 / 698 (0.57%)	1 / 566 (0.18%)	6 / 572 (1.05%)	7 / 1138 (0.62%)	6 / 1142 (0.53%)	3 / 1265 (0.24%)	10 / 1270 (0.79%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 1	0 / 6	0 / 7	0 / 6	0 / 3	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve disease
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	5 / 699 (0.72%)	5 / 698 (0.72%)	6 / 566 (1.06%)	2 / 572 (0.35%)	8 / 1138 (0.70%)	10 / 1142 (0.88%)	11 / 1265 (0.87%)	7 / 1270 (0.55%)
occurrences causally related to treatment / all	0 / 5	1 / 9	0 / 6	0 / 2	0 / 8	1 / 14	0 / 11	1 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	2 / 566 (0.35%)	0 / 572 (0.00%)	2 / 1138 (0.18%)	1 / 1142 (0.09%)	2 / 1265 (0.16%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 2	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	2 / 699 (0.29%)	1 / 698 (0.14%)	2 / 566 (0.35%)	0 / 572 (0.00%)	2 / 1138 (0.18%)	3 / 1142 (0.26%)	4 / 1265 (0.32%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 0	0 / 2	0 / 3	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 0	0 / 1	0 / 3	0 / 3	0 / 1
Cardiomyopathy
subjects affected / exposed	2 / 699 (0.29%)	2 / 698 (0.29%)	0 / 566 (0.00%)	2 / 572 (0.35%)	2 / 1138 (0.18%)	4 / 1142 (0.35%)	2 / 1265 (0.16%)	4 / 1270 (0.31%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 2	0 / 2	0 / 5	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	6 / 699 (0.86%)	9 / 698 (1.29%)	4 / 566 (0.71%)	4 / 572 (0.70%)	8 / 1138 (0.70%)	15 / 1142 (1.31%)	10 / 1265 (0.79%)	13 / 1270 (1.02%)
occurrences causally related to treatment / all	0 / 6	0 / 12	0 / 4	1 / 4	1 / 8	0 / 18	0 / 10	1 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Heart failure
subjects affected / exposed	4 / 699 (0.57%)	1 / 698 (0.14%)	2 / 566 (0.35%)	3 / 572 (0.52%)	5 / 1138 (0.44%)	5 / 1142 (0.44%)	6 / 1265 (0.47%)	4 / 1270 (0.31%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 3	0 / 3	0 / 6	0 / 5	0 / 7	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	12 / 699 (1.72%)	12 / 698 (1.72%)	11 / 566 (1.94%)	13 / 572 (2.27%)	24 / 1138 (2.11%)	24 / 1142 (2.10%)	23 / 1265 (1.82%)	25 / 1270 (1.97%)
occurrences causally related to treatment / all	0 / 12	0 / 12	0 / 11	0 / 13	0 / 24	0 / 24	0 / 23	0 / 25
deaths causally related to treatment / all	0 / 4	0 / 3	0 / 3	0 / 2	0 / 5	0 / 7	0 / 7	0 / 5
Pericardial effusion
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Right ventricular dysfunction
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	4 / 566 (0.71%)	2 / 572 (0.35%)	6 / 1138 (0.53%)	1 / 1142 (0.09%)	4 / 1265 (0.32%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 5	0 / 2	0 / 7	0 / 1	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cognitive disturbance
subjects affected / exposed	4 / 699 (0.57%)	1 / 698 (0.14%)	4 / 566 (0.71%)	2 / 572 (0.35%)	6 / 1138 (0.53%)	5 / 1142 (0.44%)	8 / 1265 (0.63%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	1 / 4	1 / 1	0 / 4	1 / 2	1 / 6	2 / 5	1 / 8	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	1 / 1
Dizziness
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 699 (0.14%)	5 / 698 (0.72%)	4 / 566 (0.71%)	0 / 572 (0.00%)	4 / 1138 (0.35%)	6 / 1142 (0.53%)	5 / 1265 (0.40%)	5 / 1270 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 7	0 / 5	0 / 0	0 / 5	0 / 8	0 / 6	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial hemorrhage
subjects affected / exposed	3 / 699 (0.43%)	2 / 698 (0.29%)	2 / 566 (0.35%)	3 / 572 (0.52%)	5 / 1138 (0.44%)	5 / 1142 (0.44%)	5 / 1265 (0.40%)	5 / 1270 (0.39%)
occurrences causally related to treatment / all	0 / 3	0 / 2	1 / 2	3 / 3	4 / 5	0 / 5	1 / 5	3 / 5
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 3	0 / 2	0 / 1
Ischemia cerebrovascular
subjects affected / exposed	10 / 699 (1.43%)	7 / 698 (1.00%)	8 / 566 (1.41%)	10 / 572 (1.75%)	18 / 1138 (1.58%)	17 / 1142 (1.49%)	18 / 1265 (1.42%)	17 / 1270 (1.34%)
occurrences causally related to treatment / all	0 / 10	0 / 7	0 / 8	1 / 13	1 / 21	0 / 17	0 / 18	1 / 20
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Memory impairment
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Motor neurone disease
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Multiple system atrophy
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Parkinson's disease
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	3 / 1265 (0.24%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 1	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyramidal tract syndrome
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spasticity
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 699 (0.43%)	1 / 698 (0.14%)	2 / 566 (0.35%)	1 / 572 (0.17%)	3 / 1138 (0.26%)	4 / 1142 (0.35%)	5 / 1265 (0.40%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 2	0 / 1	0 / 3	0 / 4	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischemic attacks
subjects affected / exposed	3 / 699 (0.43%)	5 / 698 (0.72%)	4 / 566 (0.71%)	6 / 572 (1.05%)	10 / 1138 (0.88%)	8 / 1142 (0.70%)	7 / 1265 (0.55%)	11 / 1270 (0.87%)
occurrences causally related to treatment / all	0 / 3	0 / 5	0 / 5	0 / 6	0 / 11	0 / 8	0 / 8	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vasovagal reaction
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 699 (0.29%)	4 / 698 (0.57%)	7 / 566 (1.24%)	1 / 572 (0.17%)	8 / 1138 (0.70%)	6 / 1142 (0.53%)	9 / 1265 (0.71%)	5 / 1270 (0.39%)
occurrences causally related to treatment / all	0 / 2	0 / 4	7 / 7	0 / 1	7 / 8	0 / 6	7 / 9	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Spleen disorder
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	1 / 2	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	1 / 566 (0.18%)	2 / 572 (0.35%)	3 / 1138 (0.26%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 3	0 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vestibular disorder
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal detachment
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vitreous hemorrhage
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	2 / 572 (0.35%)	2 / 1138 (0.18%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	1 / 2	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	3 / 699 (0.43%)	3 / 698 (0.43%)	7 / 566 (1.24%)	3 / 572 (0.52%)	10 / 1138 (0.88%)	6 / 1142 (0.53%)	10 / 1265 (0.79%)	6 / 1270 (0.47%)
occurrences causally related to treatment / all	0 / 3	0 / 3	1 / 7	0 / 3	1 / 10	0 / 6	1 / 10	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bloating
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cameron Ulcer
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	3 / 572 (0.52%)	3 / 1138 (0.26%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 3	1 / 3	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colonic hemorrhage
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colonic obstruction
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colonic perforation
subjects affected / exposed	1 / 699 (0.14%)	2 / 698 (0.29%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	3 / 1142 (0.26%)	2 / 1265 (0.16%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 1	0 / 2	0 / 3	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 699 (0.14%)	2 / 698 (0.29%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	3 / 1142 (0.26%)	2 / 1265 (0.16%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 1	0 / 2	0 / 3	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	3 / 699 (0.43%)	2 / 698 (0.29%)	2 / 566 (0.35%)	2 / 572 (0.35%)	4 / 1138 (0.35%)	5 / 1142 (0.44%)	5 / 1265 (0.40%)	4 / 1270 (0.31%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 2	0 / 3	0 / 5	0 / 5	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal hemorrhage
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	2 / 572 (0.35%)	2 / 1138 (0.18%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	1 / 2	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	2 / 1142 (0.18%)	2 / 1265 (0.16%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 2	0 / 1	1 / 1	0 / 1	1 / 2	0 / 3	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	2 / 699 (0.29%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	3 / 1142 (0.26%)	2 / 1265 (0.16%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 3	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal haemorrhage
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	2 / 566 (0.35%)	1 / 572 (0.17%)	3 / 1138 (0.26%)	1 / 1142 (0.09%)	3 / 1265 (0.24%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2	1 / 1	2 / 3	0 / 1	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal obstruction
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	2 / 566 (0.35%)	1 / 572 (0.17%)	3 / 1138 (0.26%)	2 / 1142 (0.18%)	4 / 1265 (0.32%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3	0 / 1	0 / 4	0 / 3	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal pain
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	2 / 566 (0.35%)	0 / 572 (0.00%)	2 / 1138 (0.18%)	0 / 1142 (0.00%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	2 / 566 (0.35%)	0 / 572 (0.00%)	2 / 1138 (0.18%)	1 / 1142 (0.09%)	2 / 1265 (0.16%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 3	1 / 2	0 / 0	1 / 2	0 / 3	1 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	2 / 566 (0.35%)	2 / 572 (0.35%)	4 / 1138 (0.35%)	2 / 1142 (0.18%)	3 / 1265 (0.24%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 2	2 / 2	3 / 4	0 / 2	1 / 3	2 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Gastritis
subjects affected / exposed	0 / 699 (0.00%)	2 / 698 (0.29%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1	0 / 2	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 699 (0.29%)	5 / 698 (0.72%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	7 / 1142 (0.61%)	2 / 1265 (0.16%)	6 / 1270 (0.47%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 0	0 / 1	0 / 1	0 / 7	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal pain
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemorrhoidal hemorrhage
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	2 / 566 (0.35%)	1 / 572 (0.17%)	3 / 1138 (0.26%)	0 / 1142 (0.00%)	2 / 1265 (0.16%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 1	1 / 3	0 / 0	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemorrhoids
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileal obstruction
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic Colitis
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mallory-Weiss tear
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	5 / 699 (0.72%)	3 / 698 (0.43%)	4 / 566 (0.71%)	5 / 572 (0.87%)	9 / 1138 (0.79%)	8 / 1142 (0.70%)	9 / 1265 (0.71%)	8 / 1270 (0.63%)
occurrences causally related to treatment / all	0 / 10	0 / 3	0 / 4	0 / 5	0 / 9	0 / 13	0 / 14	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Rectal haemorrhage
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	2 / 572 (0.35%)	2 / 1138 (0.18%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 2	1 / 2	0 / 1	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1	0 / 1	0 / 3	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 699 (0.14%)	2 / 698 (0.29%)	2 / 566 (0.35%)	2 / 572 (0.35%)	4 / 1138 (0.35%)	3 / 1142 (0.26%)	3 / 1265 (0.24%)	4 / 1270 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 3	1 / 2	2 / 2	3 / 4	0 / 4	1 / 3	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	2 / 566 (0.35%)	4 / 572 (0.70%)	6 / 1138 (0.53%)	1 / 1142 (0.09%)	2 / 1265 (0.16%)	5 / 1270 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	1 / 4	1 / 7	0 / 1	0 / 3	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Alcoholic Hepatitis
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stenosis
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	6 / 699 (0.86%)	3 / 698 (0.43%)	6 / 566 (1.06%)	7 / 572 (1.22%)	13 / 1138 (1.14%)	9 / 1142 (0.79%)	12 / 1265 (0.95%)	10 / 1270 (0.79%)
occurrences causally related to treatment / all	0 / 6	0 / 4	0 / 7	0 / 8	0 / 15	0 / 10	0 / 13	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder necrosis
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Gallbladder pain
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder perforation
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 699 (0.00%)	3 / 698 (0.43%)	4 / 566 (0.71%)	0 / 572 (0.00%)	4 / 1138 (0.35%)	3 / 1142 (0.26%)	4 / 1265 (0.32%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4	0 / 0	0 / 4	0 / 4	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 4	0 / 0	0 / 4	0 / 2	0 / 4	0 / 2
Skin and subcutaneous tissue disorders
Skin ulcer
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 699 (0.14%)	2 / 698 (0.29%)	1 / 566 (0.18%)	2 / 572 (0.35%)	3 / 1138 (0.26%)	3 / 1142 (0.26%)	2 / 1265 (0.16%)	4 / 1270 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 2	0 / 3	0 / 3	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	2 / 699 (0.29%)	1 / 698 (0.14%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	3 / 1142 (0.26%)	2 / 1265 (0.16%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	1 / 1	1 / 1	0 / 3	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	3 / 699 (0.43%)	1 / 698 (0.14%)	0 / 566 (0.00%)	2 / 572 (0.35%)	2 / 1138 (0.18%)	4 / 1142 (0.35%)	3 / 1265 (0.24%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 2	0 / 2	0 / 4	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal calculi
subjects affected / exposed	2 / 699 (0.29%)	1 / 698 (0.14%)	2 / 566 (0.35%)	0 / 572 (0.00%)	2 / 1138 (0.18%)	3 / 1142 (0.26%)	4 / 1265 (0.32%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 0	0 / 2	0 / 3	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	3 / 699 (0.43%)	1 / 698 (0.14%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	4 / 1142 (0.35%)	4 / 1265 (0.32%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0	0 / 1	0 / 4	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	2 / 699 (0.29%)	3 / 698 (0.43%)	1 / 566 (0.18%)	2 / 572 (0.35%)	3 / 1138 (0.26%)	5 / 1142 (0.44%)	3 / 1265 (0.24%)	5 / 1270 (0.39%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1	0 / 2	0 / 3	0 / 5	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypothyroidism
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	2 / 1142 (0.18%)	3 / 1265 (0.24%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 1	0 / 2	0 / 3	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Avascular necrosis
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 699 (0.00%)	2 / 698 (0.29%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 1	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical Spondylosis
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hernia
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	2 / 566 (0.35%)	2 / 572 (0.35%)	4 / 1138 (0.35%)	0 / 1142 (0.00%)	2 / 1265 (0.16%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 4	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint range of motion decreased cervical spine
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mortons neuroma
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle weakness lower limb
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoporosis
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anorectal infection
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	2 / 572 (0.35%)	2 / 1138 (0.18%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 699 (0.00%)	2 / 698 (0.29%)	0 / 566 (0.00%)	3 / 572 (0.52%)	3 / 1138 (0.26%)	2 / 1142 (0.18%)	0 / 1265 (0.00%)	5 / 1270 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 3	0 / 3	0 / 2	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Biliary tract infection
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder infection
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	2 / 1265 (0.16%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone infection
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	3 / 699 (0.43%)	6 / 698 (0.86%)	5 / 566 (0.88%)	4 / 572 (0.70%)	9 / 1138 (0.79%)	9 / 1142 (0.79%)	8 / 1265 (0.63%)	10 / 1270 (0.79%)
occurrences causally related to treatment / all	0 / 3	0 / 6	0 / 5	3 / 6	3 / 11	0 / 9	0 / 8	3 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye infection
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic infection
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inner Ear Infection
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Intestinal parasite
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint infection
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Kidney infection
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	19 / 699 (2.72%)	12 / 698 (1.72%)	9 / 566 (1.59%)	16 / 572 (2.80%)	25 / 1138 (2.20%)	31 / 1142 (2.71%)	28 / 1265 (2.21%)	28 / 1270 (2.20%)
occurrences causally related to treatment / all	0 / 24	0 / 15	0 / 14	0 / 27	0 / 41	0 / 39	0 / 38	0 / 42
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 2	0 / 3	0 / 3	0 / 4	0 / 2
Pharyngitis
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Prostate infection
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psoas abscess
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	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	0 / 0	0 / 0	0 / 0
Salivary gland infection
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 3	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Scrotal infection
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	2 / 572 (0.35%)	2 / 1138 (0.18%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 2	0 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	2 / 1265 (0.16%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	7 / 699 (1.00%)	7 / 698 (1.00%)	2 / 566 (0.35%)	5 / 572 (0.87%)	7 / 1138 (0.62%)	14 / 1142 (1.23%)	9 / 1265 (0.71%)	12 / 1270 (0.94%)
occurrences causally related to treatment / all	0 / 7	0 / 10	0 / 2	0 / 5	0 / 7	0 / 17	0 / 9	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	2 / 572 (0.35%)	2 / 1138 (0.18%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	2 / 1270 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory infection
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	4 / 699 (0.57%)	0 / 698 (0.00%)	4 / 566 (0.71%)	7 / 572 (1.22%)	11 / 1138 (0.97%)	4 / 1142 (0.35%)	8 / 1265 (0.63%)	7 / 1270 (0.55%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 5	0 / 7	0 / 12	0 / 4	0 / 9	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
Wound infection
subjects affected / exposed	3 / 699 (0.43%)	3 / 698 (0.43%)	1 / 566 (0.18%)	0 / 572 (0.00%)	1 / 1138 (0.09%)	6 / 1142 (0.53%)	4 / 1265 (0.32%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 1	0 / 0	0 / 1	0 / 6	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 699 (0.00%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0
Hyperglycemia
subjects affected / exposed	2 / 699 (0.29%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	4 / 1142 (0.35%)	2 / 1265 (0.16%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 1	0 / 4	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalemia
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperuricemia
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycemia
subjects affected / exposed	1 / 699 (0.14%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	1 / 1142 (0.09%)	1 / 1265 (0.08%)	0 / 1270 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalemia
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	1 / 566 (0.18%)	1 / 572 (0.17%)	2 / 1138 (0.18%)	0 / 1142 (0.00%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1	1 / 2	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypomagnesemia
subjects affected / exposed	0 / 699 (0.00%)	2 / 698 (0.29%)	0 / 566 (0.00%)	1 / 572 (0.17%)	1 / 1138 (0.09%)	2 / 1142 (0.18%)	0 / 1265 (0.00%)	3 / 1270 (0.24%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0	1 / 1	1 / 1	3 / 3	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatremia
subjects affected / exposed	1 / 699 (0.14%)	1 / 698 (0.14%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	2 / 1142 (0.18%)	1 / 1265 (0.08%)	1 / 1270 (0.08%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	1 / 2	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Arm A	Arm B	Arm C	Arm D	Aspirin	No Aspirin	Low Dose PPI	High Dose PPI
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 699 (0.00%)	0 / 698 (0.00%)	0 / 566 (0.00%)	0 / 572 (0.00%)	0 / 1138 (0.00%)	0 / 1142 (0.00%)	0 / 1265 (0.00%)	0 / 1270 (0.00%)

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

01 Sep 2004

Note that amendments to add sites or change Principal Investigators at active sites have not been listed here.

10 Sep 2004

Changes to GP letter, PIS and Patient Study Card

01 Nov 2004

Changes to MREC form, ICF, recruitment flow chart, PIS, GP letter and Patient Study Card

01 Feb 2005

Changes to ICF, PIS and Patient Study Card

23 Mar 2005

Drug Distribution

27 Jul 2005

Protocol_V5 & PIS_V6 Update

17 Aug 2005

Change of Sponsor from Leicester to Oxford

20 Jan 2006

Protocol_V6 & Supporting Doc

17 Jul 2006

Poster

19 Jan 2007

Drug labelling

05 Feb 2007

Protocol_V7 & Supporting Docs

09 Jul 2007

Poster

22 Aug 2007

Protocol_V8

25 Sep 2007

Protocol_V9 & Supporting Documents

04 Apr 2008

Drug labelling

01 Sep 2008

Appointment of joint CI

10 Sep 2008

Recruitment extension

23 Oct 2009

Drug distribution in Northern Ireland

31 Mar 2010

Letter for patients with overdue endoscopy

30 Jul 2010

Protocol_V10 & Supporting Documents

02 Feb 2011

Patient Newsetter

09 May 2014

End of trial PIS and GP letter

20 Jan 2015

Protocol_V11.0 & Supporting_Documents

26 Jan 2016

Protocol_V12.0 & Supporting Documents

23 Mar 2016

Patient Newsletter & PIS V14.0

05 Apr 2016

Drug labelling

14 Jun 2017

EndOfTrial_PatientLetter

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

http://www.ncbi.nlm.nih.gov/pubmed/30057104

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Clinical trials

Clinical Trial Results:
AspECT - A phase III, randomised study of aspirin and esomeprazole chemoprevention in Barrett's metaplasia & oesophagitis.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: First event of death, oesophegeal adenocarcinoma, high grade dysplasia

Primary: First event of death, oesophegeal adenocarcinoma, high grade dysplasia

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: AspECT - A phase III, randomised study of aspirin and esomeprazole chemoprevention in Barrett's metaplasia & oesophagitis.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: First event of death, oesophegeal adenocarcinoma, high grade dysplasia

Primary: First event of death, oesophegeal adenocarcinoma, high grade dysplasia

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
AspECT - A phase III, randomised study of aspirin and esomeprazole chemoprevention in Barrett's metaplasia & oesophagitis.