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Clinical Trial Results:
A Randomized, Double-Blind, Multi-Center, Parallel Group Study to Assess the Efficacy and Safety of PT010 Relative to PT003 and PT009 on COPD Exacerbations over a 52-Week Treatment Period in Subjects With Moderate to Very Severe COPD

Summary
EudraCT number	2014-005671-92
Trial protocol	NL AT DE BE PL HU CZ SE ES IT
Global end of trial date	26 Jul 2019

Results information
Results version number	v1(current)
This version publication date	01 Oct 2020
First version publication date	01 Oct 2020
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

PT010005

ISRCTN number

-

US NCT number

NCT02465567

WHO universal trial number (UTN)

-

Sponsor organisation name

Pearl Therapeutics Inc

Sponsor organisation address

200 Cardinal Way, Redwood City, California, United States, 94063

Public contact

Pearl Therapeutics Inc, Pearl Therapeutics Inc, 1 18772409479, information.center@astrazeneca.com

Scientific contact

Pearl Therapeutics Inc, Pearl Therapeutics Inc, 1 18772409479, information.center@astrazeneca.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

26 Jul 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

26 Jul 2019

Global end of trial reached?

Yes

Global end of trial date

26 Jul 2019

Was the trial ended prematurely?

No

Main objective of the trial

Efficacy and Safety

Protection of trial subjects

All subjects were put on active treatment for the duration of the study. Ventolin HFA was provided throughout the study for subjects to take as needed for relief of symptoms. Antibiotics and corticosteroids were allowed for use to treat COPD exacerbation during the study.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

15 Jul 2015

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 802

Country: Number of subjects enrolled

Australia: 68

Country: Number of subjects enrolled

Austria: 272

Country: Number of subjects enrolled

Belgium: 61

Country: Number of subjects enrolled

Canada: 171

Country: Number of subjects enrolled

Chile: 274

Country: Number of subjects enrolled

China: 533

Country: Number of subjects enrolled

Czech Republic: 105

Country: Number of subjects enrolled

France: 28

Country: Number of subjects enrolled

Germany: 1198

Country: Number of subjects enrolled

Hungary: 97

Country: Number of subjects enrolled

Italy: 40

Country: Number of subjects enrolled

Japan: 7

Country: Number of subjects enrolled

Mexico: 52

Country: Number of subjects enrolled

Netherlands: 95

Country: Number of subjects enrolled

New Zealand: 92

Country: Number of subjects enrolled

Peru: 191

Country: Number of subjects enrolled

Poland: 101

Country: Number of subjects enrolled

Russian Federation: 95

Country: Number of subjects enrolled

Serbia: 463

Country: Number of subjects enrolled

South Africa: 280

Country: Number of subjects enrolled

Spain: 209

Country: Number of subjects enrolled

Sweden: 35

Country: Number of subjects enrolled

Taiwan: 47

Country: Number of subjects enrolled

United Kingdom: 195

Country: Number of subjects enrolled

United States: 3077

Worldwide total number of subjects

8588

EEA total number of subjects

2436

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

4117

From 65 to 84 years

4471

85 years and over

0

Subject disposition

Top of page

Recruitment details

This study was conducted in 26 countries between July 2015 and July 2019.

Screening details

Subjects who successfully complete the Screening Period will then be randomized in a 1:1:1:1 scheme to BGF MDI 320/14.4/9.6 μg BID, BGF MDI 160/14.4/9.6 μg BID, BFF MDI 320/9.6 μg BID, or GFF MDI 14.4/9.6 μg BID, respectively.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Data analyst, Assessor

Are arms mutually exclusive

Yes

BGF MDI 320/14.4/9.6 μg

Arm description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Arm type

Experimental

Investigational medicinal product name

Budesonide, Glycopyrronium, and Formoterol Fumarate

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Metered Dose Inhalation 320/14.4/9.6 μg

BGF MDI 160/14.4/9.6 μg

Arm description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Arm type

Experimental

Investigational medicinal product name

Budesonide, Glycopyrronium, and Formoterol Fumarate

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Metered Dose Inhalation 160/14.4/9.6 μg

GFF MDI 14.4/9.6 μg

Arm description

Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Arm type

Experimental

Investigational medicinal product name

Glycopyrronium, and Formoterol Fumarate

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Metered Dose Inhalation 14.4/9.6 μg

BFF MDI 320/9.6 μg

Arm description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Arm type

Experimental

Investigational medicinal product name

Budesonide, , and Formoterol Fumarate

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Metered Dose Inhalation 320/14.4/9.6 μg

Number of subjects in period 1	BGF MDI 320/14.4/9.6 μg	BGF MDI 160/14.4/9.6 μg	GFF MDI 14.4/9.6 μg	BFF MDI 320/9.6 μg
Started	2157	2137	2143	2151
Completed	1708	1713	1580	1643
Not completed	449	424	563	508
Administrative Reasons	12	9	11	5
Consent withdrawn by subject	104	94	123	130
Physician decision	23	33	38	28
randomized but not treated	1	5	4	5
Major Protocol Deviation	24	26	22	25
Adverse event, non-fatal	118	113	147	138
Protocol Specified Criteria	20	10	9	12
Enrolled in more than one study	18	11	19	15
Missing PI Signature	1	-	-	-
Lost to follow-up	25	21	19	15
Lack of efficacy	103	102	171	135

Baseline characteristics

Top of page

Reporting group title

BGF MDI 320/14.4/9.6 μg

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Reporting group title

BGF MDI 160/14.4/9.6 μg

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Reporting group title

GFF MDI 14.4/9.6 μg

Reporting group description

Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Reporting group title

BFF MDI 320/9.6 μg

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Reporting group values	BGF MDI 320/14.4/9.6 μg	BGF MDI 160/14.4/9.6 μg	GFF MDI 14.4/9.6 μg	BFF MDI 320/9.6 μg	Total
Number of subjects	2157	2137	2143	2151	8588
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)	1046	1038	1000	1033	4117
From 65-84 years	1111	1099	1143	1118	4471
85 years and over	0	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	64.6 ( 7.6 )	64.6 ( 7.6 )	64.8 ( 7.6 )	64.6 ( 7.6 )	-
Sex: Female, Male
Units: Participants
Female	887	831	887	861	3466
Male	1270	1306	1256	1290	5122
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	33	40	30	39	142
Asian	162	166	157	166	651
Native Hawaiian or Other Pacific Islander	2	0	0	0	2
Black or African American	80	92	77	67	316
White	1836	1795	1829	1833	7293
More than one race	0	0	0	0	0
Unknown or Not Reported	44	44	50	46	184
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	413	403	442	411	1669
Not Hispanic or Latino	1697	1686	1656	1693	6732
Unknown or Not Reported	47	48	45	47	187

End points

Top of page

Reporting group title

BGF MDI 320/14.4/9.6 μg

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Reporting group title

BGF MDI 160/14.4/9.6 μg

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Reporting group title

GFF MDI 14.4/9.6 μg

Reporting group description

Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Reporting group title

BFF MDI 320/9.6 μg

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation

Primary: Treatment rate ratio

Top of page

End point title

Treatment rate ratio

End point description

Rate of moderate or severe COPD exacerbations

End point type

Primary

End point timeframe

52-week treatment period

End point values	BGF MDI 320/14.4/9.6 μg	BGF MDI 160/14.4/9.6 μg	GFF MDI 14.4/9.6 μg	BFF MDI 320/9.6 μg
Number of subjects analysed	1026	1013	1056	1085
Units: adjusted rate ratio (comparisons)
number (confidence interval 95%)
BGF MDI 320/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	0.76 (0.69 to 0.83)	0.87 (0.79 to 0.95)
BGF MDI 160/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	0.75 (0.69 to 0.83)	0.86 (0.79 to 0.95)

Rate of moderate or severe COPD exacerbations

Comparison groups

BGF MDI 320/14.4/9.6 μg v BGF MDI 160/14.4/9.6 μg

Number of subjects included in analysis

2039

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≥ 0.9328

Method

Mixed models analysis

Parameter type

Rate Ratio

Point estimate

1

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.1

Variability estimate

Standard error of the mean

Dispersion value

0.048

Rate of moderate or severe COPD exacerbations

Comparison groups

BGF MDI 320/14.4/9.6 μg v GFF MDI 14.4/9.6 μg

Number of subjects included in analysis

2082

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≥ 0

Method

Mixed models analysis

Parameter type

Rate ratio

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

0.83

Variability estimate

Standard error of the mean

Dispersion value

0.036

Rate of moderate or severe COPD exacerbations

Comparison groups

BGF MDI 320/14.4/9.6 μg v BFF MDI 320/9.6 μg

Number of subjects included in analysis

2111

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≥ 0.0027

Method

Mixed models analysis

Parameter type

Rate Ratio

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

0.95

Variability estimate

Standard error of the mean

Dispersion value

0.041

Secondary: Time to first moderate or severe COPD exacerbation

Top of page

End point title

Time to first moderate or severe COPD exacerbation

End point description

Time to first moderate or severe COPD exacerbation

End point type

Secondary

End point timeframe

52 Weeks

End point values	BGF MDI 320/14.4/9.6 μg	BGF MDI 160/14.4/9.6 μg	GFF MDI 14.4/9.6 μg	BFF MDI 320/9.6 μg
Number of subjects analysed	1026	1013	1056	1085
Units: Months
least squares mean (confidence interval 95%)
BGF MDI 320/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	0.88 (0.0807 to 0.959)	0.887 (0.814 to 0.966)
BGF MDI 160/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	0.866 (0.794 to 0.944)	0.873 (0.801 to 0.951)

No statistical analyses for this end point

Secondary: Change from baseline in average daily rescue Ventolin HFA use

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End point title

Change from baseline in average daily rescue Ventolin HFA use

End point description

Change from baseline in average daily rescue Ventolin HFA use over 24 weeks

End point type

Secondary

End point timeframe

24 Weeks

End point values	BGF MDI 320/14.4/9.6 μg	BGF MDI 160/14.4/9.6 μg	GFF MDI 14.4/9.6 μg	BFF MDI 320/9.6 μg
Number of subjects analysed	1425	1389	1387	1426
Units: Puffs
least squares mean (confidence interval 95%)
BGF MDI 320/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	-0.51 (-0.68 to -0.34)	-0.37 (-0.54 to -0.20)
BGF MDI 160/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	-0.35 (-0.53 to -0.18)	-0.22 (-0.39 to -0.05)

No statistical analyses for this end point

Secondary: Percentage of subjects achieving a MCID of 4 units or more in SGRQ total score

Top of page

End point title

Percentage of subjects achieving a MCID of 4 units or more in SGRQ total score

End point description

Percentage of subjects achieving a minimal clinically important difference (MCID) of 4 units or more in SGRQ (St. George’s Respiratory Questionnaire) total score at Week 24

End point type

Secondary

End point timeframe

at Week 24

End point values	BGF MDI 320/14.4/9.6 μg	BGF MDI 160/14.4/9.6 μg	GFF MDI 14.4/9.6 μg	BFF MDI 320/9.6 μg
Number of subjects analysed	2137	2121	2120	2131
Units: Odds Ratio
number (confidence interval 95%)
BGF MDI 320/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	1.358 (1.199 to 1.539)	1.246 (1.100 to 1.410)
BGF MDI 160/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	1.283 (1.133 to 1.454)	1.177 (1.039 to 1.333)

No statistical analyses for this end point

Secondary: Time to death (all cause)

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End point title

Time to death (all cause)

End point description

Time to death (all cause)

End point type

Secondary

End point timeframe

52 Weeks

End point values	BGF MDI 320/14.4/9.6 μg	BGF MDI 160/14.4/9.6 μg	GFF MDI 14.4/9.6 μg	BFF MDI 320/9.6 μg
Number of subjects analysed	2137	2121	2120	2131
Units: Hazard ratio
number (confidence interval 95%)
BGF MDI 320/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	0.544 (0.340 to 0.870)	0.782 (0.472 to 1.296)
BGF MDI 160/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	0.789 (0.518 to 1.201)	1.134 (0.716 to 1.796)

No statistical analyses for this end point

Secondary: Rate of severe COPD exacerbations

Top of page

End point title

Rate of severe COPD exacerbations

End point description

Rate of severe COPD exacerbations

End point type

Secondary

End point timeframe

52 Weeks

End point values	BGF MDI 320/14.4/9.6 μg	BGF MDI 160/14.4/9.6 μg	GFF MDI 14.4/9.6 μg	BFF MDI 320/9.6 μg
Number of subjects analysed	2137	2121	2120	2131
Units: adjusted rate ratio (comparison)
number (confidence interval 95%)
BGF MDI 320/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	0.84 (0.69 to 1.03)	0.80 (0.66 to 0.97)
BGF MDI 160/14.4/9.6 μg	999999999 (999999999 to 999999999)	999999999 (999999999 to 999999999)	0.88 (0.72 to 1.08)	0.83 (0.69 to 1.01)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Serious Adverse events were collected from the time subject signed Informed Consent to the time of the final follow-up telephone call. Adverse Events were collected from the time subject was randomized

Adverse event reporting additional description

The Safety Population was defined as all subjects who were randomized to treatment and received at least 1 dose of the study drug

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

BGF MDI 320/14.4/9.6 μg

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg

Reporting group title

BGF MDI 160/14.4/9.6 μg

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg

Reporting group title

GFF MDI 14.4/9.6 μg

Reporting group description

Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg

Reporting group title

BFF MDI 320/9.6 μg

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

Serious adverse events	BGF MDI 320/14.4/9.6 μg	BGF MDI 160/14.4/9.6 μg	GFF MDI 14.4/9.6 μg	BFF MDI 320/9.6 μg
Total subjects affected by serious adverse events
subjects affected / exposed	426 / 2144 (19.87%)	445 / 2124 (20.95%)	433 / 2125 (20.38%)	440 / 2136 (20.60%)
number of deaths (all causes)	27	42	47	35
number of deaths resulting from adverse events	20	28	35	29
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant
subjects affected / exposed	4 / 2144 (0.19%)	5 / 2124 (0.24%)	2 / 2125 (0.09%)	4 / 2136 (0.19%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1	1 / 1
Prostate cancer
subjects affected / exposed	3 / 2144 (0.14%)	1 / 2124 (0.05%)	2 / 2125 (0.09%)	3 / 2136 (0.14%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	4 / 2125 (0.19%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 4	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	2 / 2144 (0.09%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	2 / 2144 (0.09%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	2 / 2125 (0.09%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	2 / 2144 (0.09%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma metastatic
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	2 / 2125 (0.09%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
Small cell lung caner
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Benign lung neoplasm
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial carcinoma
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colorectal cancer
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant palate neoplasm
subjects affected / exposed	2 / 2144 (0.09%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	2 / 2125 (0.09%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal squamous cell carcinoma
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal wall neoplasm
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute myeloid leukaemia
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma gastric
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma pancreas
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenosquamous cell lung cancer
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer in situ
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer stage IV
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer metastatic
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon neopplasm
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal lymphoma
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal cancer
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Glioblastoma
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cancer metastatic
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Invasive breast carcinoma
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal cancer
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal squamous cell carcinoma
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metasteses to bone
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to nervous system
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic bronchial carcinoma
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal cancer metastatic
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal squamous cell carcinoma
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Papillary renal cell carcinoma
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Recosigmoid cancer
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal neoplasm
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsil cancer
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-Hodgkins lymphoma
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	3 / 2125 (0.14%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	3 / 2144 (0.14%)	3 / 2124 (0.14%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	4 / 2144 (0.19%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	3 / 2125 (0.14%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	2 / 2144 (0.09%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive urgency
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iliac artery occlusion
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral Ischaemia
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Accelerated hypertension
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic arteriosclerosis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Shock Haemorrhagic
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian artery stenosis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	1 / 2144 (0.05%)	4 / 2124 (0.19%)	7 / 2125 (0.33%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 4	1 / 7	0 / 2
deaths causally related to treatment / all	1 / 1	4 / 4	7 / 7	2 / 2
Chest pain
subjects affected / exposed	3 / 2144 (0.14%)	4 / 2124 (0.19%)	2 / 2125 (0.09%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
Sudden death
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	1 / 1	1 / 1	0 / 0	1 / 1
Drug withdrawal syndrome
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Capsular contracture associated with breast implant
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue inflamation
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	4 / 2144 (0.19%)	1 / 2124 (0.05%)	2 / 2125 (0.09%)	4 / 2136 (0.19%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Allergy to arthropod sting
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Type I hypersensitivity
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian Cyst
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scrotal cyst
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal leukoplakia
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	202 / 2144 (9.42%)	221 / 2124 (10.40%)	219 / 2125 (10.31%)	241 / 2136 (11.28%)
occurrences causally related to treatment / all	16 / 255	21 / 263	12 / 268	17 / 299
deaths causally related to treatment / all	3 / 3	3 / 3	2 / 2	4 / 4
Acute respiratory failure
subjects affected / exposed	14 / 2144 (0.65%)	20 / 2124 (0.94%)	20 / 2125 (0.94%)	7 / 2136 (0.33%)
occurrences causally related to treatment / all	0 / 16	0 / 20	1 / 20	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	10 / 2144 (0.47%)	9 / 2124 (0.42%)	5 / 2125 (0.24%)	9 / 2136 (0.42%)
occurrences causally related to treatment / all	0 / 10	0 / 9	0 / 5	1 / 9
deaths causally related to treatment / all	2 / 2	2 / 2	0 / 0	3 / 3
Pulmonary emboism
subjects affected / exposed	4 / 2144 (0.19%)	3 / 2124 (0.14%)	5 / 2125 (0.24%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 3	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 2144 (0.00%)	3 / 2124 (0.14%)	3 / 2125 (0.14%)	4 / 2136 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	4 / 2125 (0.19%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 2144 (0.00%)	3 / 2124 (0.14%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	3 / 2144 (0.14%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute pulmonary oedema
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic respiratory failure
subjects affected / exposed	2 / 2144 (0.09%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	2 / 2125 (0.09%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal polyp
subjects affected / exposed	2 / 2144 (0.09%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Organising pneumonia
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord leukoplakia
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial secretion retention
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystic lung disease
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercapnia
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal congestion
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal turbinate hypertrophy
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleurtitic pain
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary calcification
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pnuemonia aspiration
subjects affected / exposed	2 / 2144 (0.09%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Alcohol withdrawal syndrome
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Schizoaffective disorder
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicicide attempt
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Affective disorder
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Alcoholism
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hallucination
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Persistent depressive disorder
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Troponin increased
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood folate decreased
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood magnesium decreased
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrocradiogram ST-T change
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrocardiogram abnormal
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prothrombin time abnormal
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	4 / 2144 (0.19%)	3 / 2124 (0.14%)	1 / 2125 (0.05%)	5 / 2136 (0.23%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 1	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	3 / 2144 (0.14%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	3 / 2136 (0.14%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	2 / 2125 (0.09%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	2 / 2144 (0.09%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	2 / 2125 (0.09%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal wound dehiscene
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple injuries
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural hemorrhage
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Accidental overdose
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epicondylitis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body aspiration
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body in gastrointestinal tract
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hand Fracture
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerous fracture
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Limb traumatic amputation
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ocular procedural complication
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pneumothorax
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radiation proctitis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sternal fracture
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural hematoma
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Venomous bite
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound decomposition
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Contussion
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Penetrating abdominal trauma
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumoconiosis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound evisceration
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	7 / 2144 (0.33%)	10 / 2124 (0.47%)	17 / 2125 (0.80%)	7 / 2136 (0.33%)
occurrences causally related to treatment / all	0 / 8	0 / 10	2 / 18	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
Atrial fibrilation
subjects affected / exposed	9 / 2144 (0.42%)	8 / 2124 (0.38%)	14 / 2125 (0.66%)	3 / 2136 (0.14%)
occurrences causally related to treatment / all	0 / 9	3 / 8	0 / 15	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	5 / 2144 (0.23%)	5 / 2124 (0.24%)	7 / 2125 (0.33%)	4 / 2136 (0.19%)
occurrences causally related to treatment / all	0 / 5	1 / 5	0 / 7	0 / 4
deaths causally related to treatment / all	1 / 1	1 / 1	3 / 3	1 / 1
Coronary artery disease
subjects affected / exposed	5 / 2144 (0.23%)	5 / 2124 (0.24%)	7 / 2125 (0.33%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 5	0 / 5	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	5 / 2144 (0.23%)	3 / 2124 (0.14%)	5 / 2125 (0.24%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 6	0 / 3	1 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	3 / 2144 (0.14%)	1 / 2124 (0.05%)	8 / 2125 (0.38%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 1	1 / 8	0 / 0
deaths causally related to treatment / all	3 / 3	0 / 0	7 / 7	0 / 0
Angina pectoris
subjects affected / exposed	3 / 2144 (0.14%)	0 / 2124 (0.00%)	3 / 2125 (0.14%)	5 / 2136 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 2144 (0.05%)	3 / 2124 (0.14%)	2 / 2125 (0.09%)	3 / 2136 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	3 / 2144 (0.14%)	1 / 2124 (0.05%)	3 / 2125 (0.14%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	4 / 2125 (0.19%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
Cardiorespiratory arrest
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	4 / 2125 (0.19%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	1 / 1	3 / 3	2 / 2
Acute coronary syndrome
subjects affected / exposed	1 / 2144 (0.05%)	3 / 2124 (0.14%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	1 / 1	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stress cardiomyopathy
subjects affected / exposed	0 / 2144 (0.00%)	3 / 2124 (0.14%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	2 / 2144 (0.09%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute left ventricular failure
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery occulsion
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulseless electrical activity
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atriventricular block second degree
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorder
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory distress
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiovascular disorder
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiovascular insufficency
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive heart disease
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tricuspid valve incompetence
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Trifascicular black
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cor pulmonale
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	8 / 2144 (0.37%)	2 / 2124 (0.09%)	4 / 2125 (0.19%)	3 / 2136 (0.14%)
occurrences causally related to treatment / all	0 / 8	0 / 3	0 / 4	0 / 3
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
Syncope
subjects affected / exposed	2 / 2144 (0.09%)	3 / 2124 (0.14%)	1 / 2125 (0.05%)	4 / 2136 (0.19%)
occurrences causally related to treatment / all	0 / 2	1 / 3	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	5 / 2136 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	2 / 2144 (0.09%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Siezure
subjects affected / exposed	1 / 2144 (0.05%)	4 / 2124 (0.19%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebellar infarction
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ataxia
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	2 / 2125 (0.09%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	2 / 2144 (0.09%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial aneurysm
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	2 / 2125 (0.09%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aphasia
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Brain injury
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrospinal fluid leakage
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical radiculopathy
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colloid brain cyst
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolic Cerebral infarction
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intercranial
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemorrhagic stroke
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyopercapnic coma
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intercostal neuralgia
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Monparesis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myelopathy
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ruptured cerebral aneurysm
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal claudication
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord paralysis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	3 / 2144 (0.14%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iron deficiancy anaemia
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia macrocytic
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eyelid ptosis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal vascular thrombosis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Visual impairment
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal degeneration
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 2144 (0.09%)	2 / 2124 (0.09%)	1 / 2125 (0.05%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1	1 / 2
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
Small intestine obstruction
subjects affected / exposed	2 / 2144 (0.09%)	1 / 2124 (0.05%)	2 / 2125 (0.09%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdonimal pain
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	2 / 2125 (0.09%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	2 / 2144 (0.09%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	2 / 2144 (0.09%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	2 / 2144 (0.09%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcenrn
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis microscopic
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal perforation
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer perforation
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoroidal haemorrhage
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids thrombosed
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal Infarction
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	2 / 2144 (0.09%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal polyp
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mesenteric artery stenosis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive pancreatitis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngo-oesophageal diverticulum
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal haemorrhage
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toothache
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varices oesophageal
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diaphragmatic hernia
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erosive oesophagitis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal haemorrhage
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	2 / 2144 (0.09%)	2 / 2124 (0.09%)	3 / 2125 (0.14%)	3 / 2136 (0.14%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	3 / 2144 (0.14%)	0 / 2124 (0.00%)	4 / 2125 (0.19%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	2 / 2144 (0.09%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cirrohsis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis Chronic
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis toxic
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin lesion
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Swelling face
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	2 / 2144 (0.09%)	1 / 2124 (0.05%)	3 / 2125 (0.14%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anuria
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage urinary tract
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower urinary tract symptoms
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary bladder haemorrhage
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Glomerulonephritis chronic
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal mass
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Goitre
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteorthritis
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	3 / 2125 (0.14%)	3 / 2136 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 2144 (0.09%)	1 / 2124 (0.05%)	2 / 2125 (0.09%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	2 / 2125 (0.09%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	4 / 2125 (0.19%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Costochondritis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Groin pain
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc degeneration
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal ligament
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Synovial cyst
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	61 / 2144 (2.85%)	59 / 2124 (2.78%)	35 / 2125 (1.65%)	55 / 2136 (2.57%)
occurrences causally related to treatment / all	8 / 63	3 / 64	3 / 37	4 / 57
deaths causally related to treatment / all	1 / 1	1 / 1	2 / 2	1 / 1
Sepsis
subjects affected / exposed	7 / 2144 (0.33%)	5 / 2124 (0.24%)	5 / 2125 (0.24%)	3 / 2136 (0.14%)
occurrences causally related to treatment / all	0 / 8	0 / 5	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
Cellulitis
subjects affected / exposed	4 / 2144 (0.19%)	6 / 2124 (0.28%)	4 / 2125 (0.19%)	3 / 2136 (0.14%)
occurrences causally related to treatment / all	0 / 4	0 / 6	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	4 / 2144 (0.19%)	2 / 2124 (0.09%)	2 / 2125 (0.09%)	7 / 2136 (0.33%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 2	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	3 / 2144 (0.14%)	3 / 2124 (0.14%)	3 / 2125 (0.14%)	4 / 2136 (0.19%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 2144 (0.09%)	3 / 2124 (0.14%)	4 / 2125 (0.19%)	3 / 2136 (0.14%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 2144 (0.05%)	4 / 2124 (0.19%)	2 / 2125 (0.09%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	2 / 2144 (0.09%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 2144 (0.05%)	2 / 2124 (0.09%)	1 / 2125 (0.05%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	2 / 2125 (0.09%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	2 / 2144 (0.09%)	0 / 2124 (0.00%)	2 / 2125 (0.09%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
Erysipelas
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	2 / 2125 (0.09%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	3 / 2144 (0.14%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	2 / 2144 (0.09%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	3 / 2125 (0.14%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	2 / 2136 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	2 / 2125 (0.09%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia pneumococcal
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial pyelonephritis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopulmonary aspergillosis allergic
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis infective
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Campylobacter infection
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Catheter site cellulitits
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis of male external genital organ
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colonic abscess
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Emphysematous cholecystitis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis brain stem
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis shigella
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Histoplasmosis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infected bite
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infected dermal cyst
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infective exacerbation of bronshiectasis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mastitis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Micrococcus infection
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otosalpingitis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perichondritis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia pseudomonal
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural sepsis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal infection
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metapneumovirus infection
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia streptococcal
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Fluid overload
subjects affected / exposed	0 / 2144 (0.00%)	2 / 2124 (0.09%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	2 / 2144 (0.09%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatremia
subjects affected / exposed	1 / 2144 (0.05%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abnormal loss of weight
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes melitus
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	1 / 2125 (0.05%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes melitus inadequate control
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperlipidemia
subjects affected / exposed	1 / 2144 (0.05%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired fasting glucose
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	0 / 2144 (0.00%)	1 / 2124 (0.05%)	0 / 2125 (0.00%)	0 / 2136 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vitamin B12 deficiency
subjects affected / exposed	0 / 2144 (0.00%)	0 / 2124 (0.00%)	0 / 2125 (0.00%)	1 / 2136 (0.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	BGF MDI 320/14.4/9.6 μg	BGF MDI 160/14.4/9.6 μg	GFF MDI 14.4/9.6 μg	BFF MDI 320/9.6 μg
Total subjects affected by non serious adverse events
subjects affected / exposed	337 / 2144 (15.72%)	361 / 2124 (17.00%)	292 / 2125 (13.74%)	336 / 2136 (15.73%)
Infections and infestations
Nasopharyngitis
subjects affected / exposed	227 / 2144 (10.59%)	239 / 2124 (11.25%)	199 / 2125 (9.36%)	234 / 2136 (10.96%)
occurrences all number	290	315	255	331
Upper respiratory tract infection
subjects affected / exposed	123 / 2144 (5.74%)	137 / 2124 (6.45%)	102 / 2125 (4.80%)	115 / 2136 (5.38%)
occurrences all number	149	176	129	154

More information

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Were there any global substantial amendments to the protocol? Yes

04 Jul 2015

Updated Study Design, Investigational Plan, Design figure, Rationale of Study Design , Inclusion/exclusion criteria

17 Aug 2015

Synopsis: Study Design: Paragraph, overall Design and Plan updated Secondary Efficacy Endpoints, Other Efficacy Endpoints, 24-Hour Holter Monitoring Sub-study Endpoints, Interim Efficacy Analysis, List of Abbreviations and Definitions of Terms, inclusion exclusion criteria updated

08 Jan 2016

Synopsis: Study Design: Paragraph, overall Design and Plan updated Secondary Efficacy Endpoints, Other Efficacy Endpoints, 24-Hour Holter Monitoring Sub-study Endpoints, Interim Efficacy Analysis, List of Abbreviations and Definitions of Terms, inclusion exclusion criteria updated

25 Aug 2016

Changed Sponsor Contact on title and sponsor signature page Revised Secondary Efficacy Endpoints and Other Endpoints Revised Synopsis, all descriptions of covariates in efficacy analyses "or caffeine-containing medications” as these, in addition to caffeine-containing foods and beverages, are not allowed within 6 hours of and during an in-clinic visit since they may affect lung function measurements. Revised exclusion criteria Prohibited meds revised updated treatment discontinuation

19 Sep 2016

Added additional section references for Treatment discontinuation Duration of study updated from “not expected to exceed 40 months” to “not expected to exceed 50 months” Removed other efficacy endpoints, other 24hour Holter monitoring sub-study endpoints, and healthcare resource utilization endpoints Exclusion Criterion updated Added description of medication allowed during the treatment of severe COPD exacerbations Renamed adjudication committees to the Clinical Endpoint Committee to reflect current process and terminology

03 Nov 2017

Added additional section references for Treatment discontinuation Duration of study updated from “not expected to exceed 40 months” to “not expected to exceed 50 months” Removed other efficacy endpoints, other 24hour Holter monitoring sub-study endpoints, and healthcare resource utilization endpoints Exclusion Criterion updated Added description of medication allowed during the treatment of severe COPD exacerbations Renamed adjudication committees to the Clinical Endpoint Committee to reflect current process and terminology

27 Mar 2018

Added secondary objective 24-hour Holter monitoring sub-study endpoints added Updated the definition for the duration of moderate or severe COPD exacerbations The non-inferiority (NI) margin was update Criteria for upper limit for Glucose were changed for potentially clinically significant laboratory values

21 Jun 2019

Added secondary objective 24-hour Holter monitoring sub-study endpoints added Updated the definition for the duration of moderate or severe COPD exacerbations The non-inferiority (NI) margin was update Criteria for upper limit for Glucose were changed for potentially clinically significant laboratory values

Were there any global interruptions to the trial? No

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

None reported

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