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Clinical Trial Results:
A Phase III, Multicentre, Randomized, Parallel-group, Double-blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis

Summary
EudraCT number	2010-020338-25
Trial protocol	LT ES BE FR HU NL CZ GB DE PT AT FI IT GR BG DK PL
Global end of trial date	31 Dec 2022

Results information
Results version number	v3(current)
This version publication date	03 Jan 2024
First version publication date	08 Jul 2016
Other versions	v1 , v2
Version creation reason

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

WA25046

ISRCTN number

-

US NCT number

NCT01194570

WHO universal trial number (UTN)

-

Sponsor organisation name

Hoffmann-La Roche

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, 4070

Public contact

F. Hoffmann-La Roche, Ltd, F. Hoffmann-La Roche, Ltd, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche, Ltd, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.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

31 Dec 2022

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

31 Dec 2022

Was the trial ended prematurely?

No

Main objective of the trial

This randomized, parallel group, double-blind, placebo controlled study evaluated the efficacy and safety of ocrelizumab in participants with primary progressive multiple sclerosis. Eligible participants were randomized 2 : 1 to receive either ocrelizumab or placebo.

Protection of trial subjects

This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. All participants were required to read and sign an informed consent form prior to participation in the study.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

02 Mar 2011

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 10

Country: Number of subjects enrolled

Austria: 16

Country: Number of subjects enrolled

Belgium: 5

Country: Number of subjects enrolled

Bulgaria: 3

Country: Number of subjects enrolled

Brazil: 11

Country: Number of subjects enrolled

Canada: 32

Country: Number of subjects enrolled

Switzerland: 7

Country: Number of subjects enrolled

Czechia: 20

Country: Number of subjects enrolled

Germany: 57

Country: Number of subjects enrolled

Spain: 74

Country: Number of subjects enrolled

Finland: 12

Country: Number of subjects enrolled

France: 106

Country: Number of subjects enrolled

United Kingdom: 29

Country: Number of subjects enrolled

Greece: 7

Country: Number of subjects enrolled

Hungary: 20

Country: Number of subjects enrolled

Israel: 17

Country: Number of subjects enrolled

Italy: 15

Country: Number of subjects enrolled

Lithuania: 5

Country: Number of subjects enrolled

Mexico: 6

Country: Number of subjects enrolled

Netherlands: 11

Country: Number of subjects enrolled

Norway: 1

Country: Number of subjects enrolled

New Zealand: 2

Country: Number of subjects enrolled

Peru: 5

Country: Number of subjects enrolled

Poland: 58

Country: Number of subjects enrolled

Romania: 8

Country: Number of subjects enrolled

Russian Federation: 2

Country: Number of subjects enrolled

Ukraine: 74

Country: Number of subjects enrolled

United States: 101

Country: Number of subjects enrolled

Portugal: 18

Worldwide total number of subjects

732

EEA total number of subjects

436

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)

732

From 65 to 84 years

0

85 years and over

0

Subject disposition

Top of page

Recruitment details

-

Screening details

A total of 943 participants were screened and 732 were randomized into the study, of which 725 received at least one dose of placebo or ocrelizumab.

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

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Two IV infusions of placebo matched to ocrelizumab in each treatment cycle of double blind treatment period.

Investigational medicinal product name

Ocrelizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Two IV infusions of ocrelizumab 300 mg for Cycle 1 and single IV infusion of ocrelizumab 600 mg for subsequent cycles in OLE phase.

Ocrelizumab 600 mg

Arm description

Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Two IV infusions of 300 mg in each treatment cycle of double blind treatment period; two IV infusions of ocrelizumab 300 mg for Cycle 1 and single IV infusion of ocrelizumab 600 mg for subsequent cycles in OLE phase.

Number of subjects in period 1	Placebo	Ocrelizumab 600 mg
Started	244	488
Completed	89	218
Not completed	155	270
Adverse event, serious fatal	6	20
Non-Compliance	2	2
Physician decision	10	25
Consent withdrawn by subject	57	82
Adverse event, non-fatal	22	40
Study Terminated By Sponsor	-	1
Non-Compliance With Study Drug	2	2
Not Specified	18	47
Pregnancy	1	1
Lost to follow-up	4	15
Lack of efficacy	32	33
Protocol deviation	1	2

Baseline characteristics

Top of page

Reporting group title

Placebo

Reporting group description

Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.

Reporting group title

Ocrelizumab 600 mg

Reporting group description

Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.

Reporting group values	Placebo	Ocrelizumab 600 mg	Total
Number of subjects	244	488	732
Age Categorical
Units: Participants
<=18 years	0	0	0
Between 18 and 65 years	244	488	732
>=65 years	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	44.4 ± 8.3	44.7 ± 7.9	-
Gender, Male/Female
Units:
Female	124	237	361
Male	120	251	371
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	5	5
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	5	9	14
White	235	454	689
More than one race	0	0	0
Unknown or Not Reported	4	20	24
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	14	32	46
Not Hispanic or Latino	206	385	591
Unknown or Not Reported	24	71	95

End points

Top of page

Reporting group title

Placebo

Reporting group description

Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.

Reporting group title

Ocrelizumab 600 mg

Reporting group description

Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.

Subject analysis set title

Placebo (Open Label Extension)

Subject analysis set type

Sub-group analysis

Subject analysis set description

During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.

Subject analysis set title

Ocrelizumab (Open Label Extension)

Subject analysis set type

Sub-group analysis

Subject analysis set description

During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.

Primary: Time to Onset of Clinical Disability Progression (CDP) Sustained for at least 12 Weeks During the Double-Blind Treatment Period

Top of page

End point title

Time to Onset of Clinical Disability Progression (CDP) Sustained for at least 12 Weeks During the Double-Blind Treatment Period ^[1]

End point description

The time to onset of CDP was defined as time from baseline to first disability progression, which is confirmed at next regularly scheduled visit >=12 weeks (>=84 days) after initial disability progression. Baseline for time to onset of CDP is the date of randomization, independent of the first day of dosing. Disability progression is defined as an increase of >= 1.0 point from baseline expanded disability status scale (EDSS) score, if baseline EDSS value is <=5.5 points (inclusive), or an increase of >=0.5 points, if baseline EDSS is >5.5 points. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). The randomized participants who did not receive any treatment were censored at days 0 in each Arm.

End point type

Primary

End point timeframe

Maximal follow up: 216 weeks for Placebo arm and 217 weeks for Ocrelizumab arm

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Final results

End point values	Placebo	Ocrelizumab 600 mg
Number of subjects analysed	244 ^[2]	487 ^[3]
Units: weeks
median (full range (min-max))	0000 (0 to 0000)	0000 (0 to 0000)

Notes
[2] - Not reached due to low number of participants with the event at the end of the study.
[3] - Not reached due to low number of participants with the event at the end of the study.

No statistical analyses for this end point

Secondary: Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 24 Weeks During the Double-Blind Treatment Period

Top of page

End point title

Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 24 Weeks During the Double-Blind Treatment Period

End point description

The time to onset of CDP was defined as time from baseline to first disability progression, which is confirmed at next regularly scheduled visit >=12 weeks (>=84 days) after initial disability progression. Baseline for time to onset of CDP is the date of randomization, independent of the first day of dosing. Disability progression is defined as an increase of >= 1.0 point from baseline expanded disability status scale (EDSS) score, if baseline EDSS value is <=5.5 points (inclusive), or an increase of >=0.5 points, if baseline EDSS is >5.5 points. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). The randomized participants who did not receive any treatment were censored at days 0 in each Arm.

End point type

Secondary

End point timeframe

Maximal follow up: 216 weeks for Placebo arm and 217 weeks for Ocrelizumab arm

End point values	Placebo	Ocrelizumab 600 mg
Number of subjects analysed	244 ^[4]	487 ^[5]
Units: weeks
median (full range (min-max))	0000 (0 to 0000)	0000 (0 to 0000)

Notes
[4] - Not reached due to low number of participants with the event at the end of the study.
[5] - Not reached due to low number of participants with the event at the end of the study.

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Timed 25-Foot Walk (T25-FW) at Week 120

Top of page

End point title

Percent Change From Baseline in Timed 25-Foot Walk (T25-FW) at Week 120

End point description

End point type

Secondary

End point timeframe

Baseline, Week 120

End point values	Placebo	Ocrelizumab 600 mg
Number of subjects analysed	239	473
Units: percent change
least squares mean (confidence interval 95%)	55.097 (39.855 to 71.999)	38.933 (29.222 to 49.374)

Ranked ANCOVA

Statistical analysis description

Estimates (back-transformed) based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: log(Post-baseline(BL)/BL) = log(BL 25-FTW) + Geographical Region (US vs. ROW) + Age (<=45, > 45 years) + Week + Treatment + Treatment*Week (repeated values over Week) + log (BL 25-FTW)*Week. Relative reduction was calculated as -Relative change = -(OCR response-Placebo response)/Placebo response*100%. The 95% CI for relative reduction was obtained using the Bootstrap method.

Comparison groups

Placebo v Ocrelizumab 600 mg

Number of subjects included in analysis

712

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0404 ^[6]

Method

Ranked ANCOVA

Parameter type

Relative Reduction (%)

Point estimate

29.337

Confidence interval

level

95%

sides

2-sided

lower limit

-1.618

upper limit

51.456

Notes
[6] - P-value from a ranked ANCOVA on Percent Change from BL adjusting for rank of BL 25-Foot Timed Walk (25-FTW), Geographical Region (US vs ROW) and Age (<=45, > 45 years); missing observations imputed with LOCF.

Secondary: Percent Change From Baseline in Total Volume of T2 Lesions at Week 120

Top of page

End point title

Percent Change From Baseline in Total Volume of T2 Lesions at Week 120

End point description

End point type

Secondary

End point timeframe

From Baseline to Week 120

End point values	Placebo	Ocrelizumab 600 mg
Number of subjects analysed	234	464
Units: percent change
least squares mean (confidence interval 95%)	7.426 (4.967 to 9.942)	-3.366 (-4.987 to -1.718)

Ranked ANCOVA

Statistical analysis description

Estimates (back-transformed) are based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: log(Post-BL/BL) = log(BL T2 lesion volume) + Geographical Region (US vs. ROW) + Age (<=45, > 45 years) + Week + Treatment + Treatment*Week (repeated values over Week) + log (BL T2 lesion volume)*Week.

Comparison groups

Placebo v Ocrelizumab 600 mg

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[7]

Method

Ranked ANCOVA

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.876

upper limit

0.924

Notes
[7] - P-value is from ranked ANCOVA on Percent Change from BL adjusting for rank of BL T2 lesion volume, Geographical Region (US vs ROW) and Age (<=45, > 45 years); missing observations imputed with LOCF.

Secondary: Percent Change in Total Brain Volume From Week 24 to Week 120

Top of page

End point title

Percent Change in Total Brain Volume From Week 24 to Week 120

End point description

End point type

Secondary

End point timeframe

From Week 24 to Week 120

End point values	Placebo	Ocrelizumab 600 mg
Number of subjects analysed	203	407
Units: percent change
least squares mean (confidence interval 95%)	-1.093 (-1.236 to -0.951)	-0.902 (-1.004 to -0.799)

MMRM

Statistical analysis description

Estimates are from analysis based on MMRM using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region (US vs. ROW) + Age (<=45, > 45 years) + Week + Treatment + Treatment*Week (repeated values over Week) + Brain Volume at Week 24*Week. Relative reduction was calculated as – Relative change = - (OCR response-Placebo response)/Placebo response*100%. The 95% CI for relative reduction was obtained using Bootstrap method.

Comparison groups

Placebo v Ocrelizumab 600 mg

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0206

Method

MMRM

Parameter type

Relative Reduction (%)

Point estimate

17.475

Confidence interval

level

95%

sides

2-sided

lower limit

3.206

upper limit

29.251

Secondary: Change in From Baseline Physical Component Summary Score (PCS) SF- 36 Health Survey (SF-36) at Week 120

Top of page

End point title

Change in From Baseline Physical Component Summary Score (PCS) SF- 36 Health Survey (SF-36) at Week 120

End point description

The SF-36v2 is a 36-item, self- reported, generic measure of quality of life that has been widely used in multiple disease areas. It is composed of 8 health domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The PCS score was derived based on the SF-36 V2 User's Manual. Scoring for PCS involves (a) recoding item response values, (b) summing recoded response values for all items in a given scale to obtain the scale raw score, (c) transforming scale raw score to a 0−100 score. The PCS score was computed by (a) multiplying each health domain z score by a scale-specific physical factor score coefficient, (b) summing the resulting products, (c) converting the product total to T score. The total score ranges from 0-100, higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

End point type

Secondary

End point timeframe

From Baseline to Week 120

End point values	Placebo	Ocrelizumab 600 mg
Number of subjects analysed	128	292
Units: units on a scale
least squares mean (confidence interval 95%)	-1.108 (-2.394 to 0.177)	-0.731 (-1.655 to 0.193)

MMRM

Statistical analysis description

Estimates are from analysis based on MMRM using unstructured covariance matrix: Change = Baseline PCS Score + Geographical Region (US vs. ROW) + Age (<=45, > 45 years) + Week + Treatment + Treatment*Week (repeated values over Week) + Baseline PCS Score*Week.

Comparison groups

Placebo v Ocrelizumab 600 mg

Number of subjects included in analysis

420

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6034

Method

MMRM

Parameter type

Difference in Adjusted Means

Point estimate

0.377

Confidence interval

level

95%

sides

2-sided

lower limit

-1.048

upper limit

1.802

Variability estimate

Standard error of the mean

Dispersion value

0.725

Secondary: Number of Participants With at Least one Adverse Event (AE)

Top of page

End point title

Number of Participants With at Least one Adverse Event (AE)

End point description

AEs included infusion related reactions (IRRs) and serious multiple sclerosis (MS) relapses, but excluded non-serious MS relapses.

End point type

Secondary

End point timeframe

From baseline to 9 years

End point values	Placebo	Ocrelizumab 600 mg	Placebo (Open Label Extension)	Ocrelizumab (Open Label Extension)
Number of subjects analysed	239	486	160	367
Units: Participants
Serious Adverse Events	53	99	59	167
Adverse Events	215	462	148	354

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline up to 615 weeks

Adverse event reporting additional description

The safety population included all participants who received any study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

DB PLACEBO

Reporting group description

Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks.

Reporting group title

OLE OCRELIZUMAB

Reporting group description

During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.

Reporting group title

OLE PLACEBO

Reporting group description

During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.

Reporting group title

DB OCRELIZUMAB

Reporting group description

Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.

Serious adverse events	DB PLACEBO	OLE OCRELIZUMAB	OLE PLACEBO	DB OCRELIZUMAB
Total subjects affected by serious adverse events
subjects affected / exposed	58 / 239 (24.27%)	167 / 369 (45.26%)	59 / 158 (37.34%)	104 / 486 (21.40%)
number of deaths (all causes)	7	19	4	24
number of deaths resulting from adverse events	0	3	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BORDERLINE SEROUS TUMOUR OF OVARY
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
ANAPLASTIC LARGE-CELL LYMPHOMA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
BASAL CELL CARCINOMA
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
BENIGN PANCREATIC NEOPLASM
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
BENIGN VAGINAL NEOPLASM
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	0 / 486 (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 / 1	0 / 0	0 / 0
ADENOCARCINOMA OF THE CERVIX
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
BREAST CANCER
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CHONDROMA
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
ENDOMETRIAL CANCER
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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 NEOPLASM
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
INTRADUCTAL PAPILLARY BREAST NEOPLASM
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
MALIGNANT FIBROUS HISTIOCYTOMA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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 DUCTAL BREAST CARCINOMA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	2 / 158 (1.27%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
KERATOACANTHOMA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
LIPOMA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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 ADENOCARCINOMA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 / 1	0 / 0	0 / 0
LUNG NEOPLASM MALIGNANT
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 BREAST CARCINOMA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
MENINGIOMA BENIGN
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
NODULAR MELANOMA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
PANCREATIC CARCINOMA METASTATIC
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1
PARAGANGLION NEOPLASM BENIGN
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
PARATHYROID TUMOUR BENIGN
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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 CELL CARCINOMA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
ROSAI-DORFMAN SYNDROME
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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 NEOPLASM
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
TRANSITIONAL CELL CARCINOMA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
UTERINE LEIOMYOMA
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	2 / 486 (0.41%)
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
PROSTATE CANCER
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
Vascular disorders
DEEP VEIN THROMBOSIS
subjects affected / exposed	1 / 239 (0.42%)	3 / 369 (0.81%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
DRY GANGRENE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
VARICOSE VEIN
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
HYPERTENSIVE CRISIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
PERIPHERAL ARTERY OCCLUSION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
HYPERTENSION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	0 / 486 (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
General disorders and administration site conditions
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
CATHETER SITE HAEMORRHAGE
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
CHEST PAIN
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
DRUG INTOLERANCE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
GAIT DISTURBANCE
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	2 / 486 (0.41%)
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
ASTHENIA
subjects affected / exposed	1 / 239 (0.42%)	4 / 369 (1.08%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
HYPERTHERMIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
INFLAMMATION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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-CARDIAC CHEST PAIN
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	1 / 486 (0.21%)
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
OEDEMA PERIPHERAL
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	1 / 158 (0.63%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
SUDDEN DEATH
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 / 1	0 / 0	0 / 0
SUDDEN CARDIAC DEATH
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Immune system disorders
DRUG HYPERSENSITIVITY
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
Reproductive system and breast disorders
CERVICAL POLYP
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
ENDOMETRIAL HYPERPLASIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
FIBROCYSTIC BREAST DISEASE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
INTERMENSTRUAL BLEEDING
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
UTERINE PROLAPSE
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
OVARIAN CYST TORSION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
OVARIAN CYST
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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, thoracic and mediastinal disorders
INTERSTITIAL LUNG DISEASE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
HYPERSENSITIVITY PNEUMONITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
DYSPNOEA
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
ALVEOLITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
ASPIRATION
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
BRONCHITIS CHRONIC
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
ACUTE RESPIRATORY FAILURE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	0 / 486 (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 PULMONARY OEDEMA
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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 THROMBOSIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
PULMONARY GRANULOMA
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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 EMBOLISM
subjects affected / exposed	0 / 239 (0.00%)	5 / 369 (1.36%)	1 / 158 (0.63%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
PNEUMOTHORAX SPONTANEOUS
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	0 / 486 (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
PNEUMOTHORAX
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
VOCAL CORD THICKENING
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
PLEURAL EFFUSION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
Psychiatric disorders
BEHAVIOUR DISORDER
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
ANXIETY
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
PSYCHOTIC DISORDER
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
SUICIDAL IDEATION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
SUICIDE ATTEMPT
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	3 / 486 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
MENTAL STATUS CHANGES
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
MANIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
MAJOR DEPRESSION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
DEPRESSION SUICIDAL
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
DEPRESSION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
COMPLETED SUICIDE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 / 1	0 / 0	0 / 0
Investigations
BLOOD GLUCOSE FLUCTUATION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
HELICOBACTER TEST POSITIVE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
LIVER FUNCTION TEST ABNORMAL
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
Injury, poisoning and procedural complications
ACCIDENTAL OVERDOSE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
ANKLE FRACTURE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC CONTUSION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
FRACTURED SACRUM
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
FALL
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	1 / 158 (0.63%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
FEMORAL NECK FRACTURE
subjects affected / exposed	1 / 239 (0.42%)	2 / 369 (0.54%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	2 / 239 (0.84%)	2 / 369 (0.54%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
FIBULA FRACTURE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
FRACTURE DISPLACEMENT
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
CONTUSION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
HEAD INJURY
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
POST LUMBAR PUNCTURE SYNDROME
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
HIP FRACTURE
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	1 / 158 (0.63%)	0 / 486 (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
HUMERUS FRACTURE
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
INCISION SITE IMPAIRED HEALING
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
INFUSION RELATED REACTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	5 / 486 (1.03%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
JOINT DISLOCATION
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
LUMBAR VERTEBRAL FRACTURE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
MULTIPLE FRACTURES
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
OVERDOSE
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
PATELLA FRACTURE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
PELVIC FRACTURE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 FEVER
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
POST PROCEDURAL HAEMATURIA
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
RADIUS FRACTURE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
ROAD TRAFFIC ACCIDENT
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
TENDON RUPTURE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	2 / 486 (0.41%)
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
SUBDURAL HAEMATOMA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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 HAEMORRHAGE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
SKIN LACERATION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
THORACIC VERTEBRAL FRACTURE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
TIBIA FRACTURE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
TOXICITY TO VARIOUS AGENTS
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
WOUND DEHISCENCE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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	0 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	0 / 486 (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
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
ANGINA UNSTABLE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
ATRIAL FIBRILLATION
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
BUNDLE BRANCH BLOCK LEFT
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
CARDIAC ARREST
subjects affected / exposed	0 / 239 (0.00%)	3 / 369 (0.81%)	1 / 158 (0.63%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
TACHYCARDIA
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
CARDIOMYOPATHY
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 / 1	0 / 0	0 / 0
CORONARY ARTERY INSUFFICIENCY
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 / 1	0 / 0	0 / 0
MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	2 / 486 (0.41%)
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
MYOCARDIAL ISCHAEMIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 / 1	0 / 0	0 / 0
SINUS TACHYCARDIA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
CARDIAC FAILURE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
Nervous system disorders
CEREBRAL INFARCTION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
CEREBRAL ISCHAEMIA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	2 / 158 (1.27%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
EMBOLIC STROKE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
EPILEPSY
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
GENERALISED TONIC-CLONIC SEIZURE
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	0 / 486 (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
MIGRAINE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
INTRACRANIAL ANEURYSM
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
INTRACRANIAL PRESSURE INCREASED
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
LUMBAR RADICULOPATHY
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
HEADACHE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
MIGRAINE WITH AURA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
MULTIPLE SCLEROSIS
subjects affected / exposed	0 / 239 (0.00%)	4 / 369 (1.08%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
MULTIPLE SCLEROSIS PSEUDO RELAPSE
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
MULTIPLE SCLEROSIS RELAPSE
subjects affected / exposed	2 / 239 (0.84%)	4 / 369 (1.08%)	0 / 158 (0.00%)	4 / 486 (0.82%)
occurrences causally related to treatment / all	1 / 2	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
MUSCLE SPASTICITY
subjects affected / exposed	2 / 239 (0.84%)	3 / 369 (0.81%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
NERVOUS SYSTEM DISORDER
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
OPTIC NEURITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	1 / 486 (0.21%)
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
PARALYSIS
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
PARAPARESIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
PARKINSON'S DISEASE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
PARTIAL SEIZURES WITH SECONDARY GENERALISATION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
PRESYNCOPE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
SCIATICA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
SEIZURE
subjects affected / exposed	2 / 239 (0.84%)	2 / 369 (0.54%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 2	0 / 7	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
STATUS EPILEPTICUS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
SUBARACHNOID HAEMORRHAGE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
TRANSIENT ISCHAEMIC ATTACK
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
UHTHOFF'S PHENOMENON
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	0 / 486 (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
TRIGEMINAL NEURALGIA
subjects affected / exposed	1 / 239 (0.42%)	2 / 369 (0.54%)	2 / 158 (1.27%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
AGRANULOCYTOSIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
ANAEMIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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 MEGALOBLASTIC
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
NEUTROPENIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
IRON DEFICIENCY ANAEMIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
MICROCYTIC ANAEMIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
FEBRILE NEUTROPENIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
CATARACT
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	2 / 486 (0.41%)
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
EPIRETINAL MEMBRANE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
EYE INFLAMMATION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
GLAUCOMA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
RETINAL DISORDER
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
Gastrointestinal disorders
APHTHOUS ULCER
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
ABDOMINAL PAIN LOWER
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
ANAL FISSURE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
ANAL POLYP
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
ANORECTAL VARICES
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
ABDOMINAL PAIN
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
COLITIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
COLITIS ISCHAEMIC
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	2 / 239 (0.84%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
CROHN'S DISEASE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
DIARRHOEA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
GASTRIC ULCER HAEMORRHAGE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
DUODENAL ULCER
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	0 / 486 (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
FAECALOMA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
GASTRIC FISTULA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
DIVERTICULUM
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
GASTRITIS EROSIVE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
GASTROINTESTINAL INFLAMMATION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
GASTROINTESTINAL POLYP HAEMORRHAGE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
ILEUS
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
INCARCERATED UMBILICAL HERNIA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
PANCREATITIS ACUTE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	2 / 486 (0.41%)
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
INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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 INTESTINE POLYP
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
NAUSEA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
OESOPHAGEAL RUPTURE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
PANCREATITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
INGUINAL HERNIA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
UMBILICAL HERNIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
UPPER GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
VOLVULUS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	0 / 486 (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
VOMITING
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
Hepatobiliary disorders
CHOLECYSTITIS CHRONIC
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	1 / 486 (0.21%)
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
BILE DUCT STENOSIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
CHOLANGITIS
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	0 / 486 (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
CHOLECYSTITIS ACUTE
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
DRUG-INDUCED LIVER INJURY
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
HEPATITIS ACUTE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
HEPATITIS TOXIC
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
CHOLELITHIASIS
subjects affected / exposed	1 / 239 (0.42%)	2 / 369 (0.54%)	1 / 158 (0.63%)	1 / 486 (0.21%)
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
Skin and subcutaneous tissue disorders
PRURITUS ALLERGIC
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
ACTINIC KERATOSIS
subjects affected / exposed	2 / 239 (0.84%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
DECUBITUS ULCER
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
DERMATITIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
LICHEN PLANUS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
RASH
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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 and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CALCULUS URINARY
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
BLADDER PERFORATION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
URETHRAL STENOSIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
URINARY RETENTION
subjects affected / exposed	2 / 239 (0.84%)	3 / 369 (0.81%)	1 / 158 (0.63%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CYSTITIS HAEMORRHAGIC
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
TUBULOINTERSTITIAL NEPHRITIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
PROTEINURIA
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
NEPHROLITHIASIS
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	1 / 158 (0.63%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
HYDRONEPHROSIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
HAEMATURIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
BACK PAIN
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	4 / 486 (0.82%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CHONDROPATHY
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
MUSCLE SPASMS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
RHABDOMYOLYSIS
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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 CHEST PAIN
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
OSTEOARTHRITIS
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
PAIN IN EXTREMITY
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
POLYARTHRITIS
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
MUSCULAR WEAKNESS
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
ROTATOR CUFF SYNDROME
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
SERONEGATIVE ARTHRITIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
SPINAL PAIN
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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 STENOSIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
TENDONITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
Infections and infestations
ABSCESS OF EYELID
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
ANAL ABSCESS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
APPENDICITIS
subjects affected / exposed	0 / 239 (0.00%)	3 / 369 (0.81%)	2 / 158 (1.27%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	0 / 0	1 / 3	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
APPENDICITIS PERFORATED
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
ARTHRITIS INFECTIVE
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
ABSCESS LIMB
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
BACTERIAL INFECTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
BACTERIAL PYELONEPHRITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
BORRELIA INFECTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
BRONCHIOLITIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
BRONCHITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 239 (0.00%)	12 / 369 (3.25%)	2 / 158 (1.27%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 12	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CANDIDA SEPSIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
CELLULITIS
subjects affected / exposed	0 / 239 (0.00%)	5 / 369 (1.36%)	2 / 158 (1.27%)	3 / 486 (0.62%)
occurrences causally related to treatment / all	0 / 0	5 / 8	3 / 6	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS INFECTIVE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
CLOSTRIDIUM DIFFICILE INFECTION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
BURSITIS INFECTIVE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
COVID-19 PNEUMONIA
subjects affected / exposed	0 / 239 (0.00%)	31 / 369 (8.40%)	5 / 158 (3.16%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	8 / 31	1 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	2 / 5	0 / 0	0 / 0
CYSTITIS
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
DENGUE FEVER
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
DIVERTICULITIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	1 / 486 (0.21%)
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
ENCEPHALITIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 / 1	0 / 0	0 / 0
GASTROINTESTINAL INFECTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
ERYSIPELAS
subjects affected / exposed	0 / 239 (0.00%)	3 / 369 (0.81%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA URINARY TRACT INFECTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
GANGRENE
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS VIRAL
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
EPIDIDYMITIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
HEPATITIS VIRAL
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
HERPES OPHTHALMIC
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
IMPETIGO
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
INFECTED DERMAL CYST
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
INFLUENZA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
ORCHITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
MASTITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
MENINGITIS ASEPTIC
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
MENINGITIS BACTERIAL
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
NEUTROPENIC SEPSIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
LARGE INTESTINE INFECTION
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
OSTEOMYELITIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	1 / 158 (0.63%)	0 / 486 (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
OTITIS EXTERNA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
PELVIC INFLAMMATORY DISEASE
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
PERITONITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
PNEUMONIA
subjects affected / exposed	3 / 239 (1.26%)	17 / 369 (4.61%)	3 / 158 (1.90%)	6 / 486 (1.23%)
occurrences causally related to treatment / all	1 / 4	8 / 18	0 / 4	4 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
PYELONEPHRITIS
subjects affected / exposed	1 / 239 (0.42%)	3 / 369 (0.81%)	0 / 158 (0.00%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	1 / 1	3 / 4	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA BACTERIAL
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
PNEUMONIA ESCHERICHIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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 INFECTION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
POST PROCEDURAL SEPSIS
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
PYELOCYSTITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
PNEUMONIA ASPIRATION
subjects affected / exposed	0 / 239 (0.00%)	3 / 369 (0.81%)	1 / 158 (0.63%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
PYELONEPHRITIS ACUTE
subjects affected / exposed	0 / 239 (0.00%)	4 / 369 (1.08%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 0	3 / 4	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	0 / 239 (0.00%)	7 / 369 (1.90%)	2 / 158 (1.27%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	0 / 0	5 / 10	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
SEPTIC SHOCK
subjects affected / exposed	1 / 239 (0.42%)	1 / 369 (0.27%)	1 / 158 (0.63%)	0 / 486 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
SINUSITIS
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
SUSPECTED COVID-19
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	0 / 486 (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 / 1	0 / 0	0 / 0
TOOTH INFECTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
URINARY TRACT INFECTION
subjects affected / exposed	4 / 239 (1.67%)	20 / 369 (5.42%)	7 / 158 (4.43%)	4 / 486 (0.82%)
occurrences causally related to treatment / all	1 / 5	9 / 28	1 / 10	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
UROSEPSIS
subjects affected / exposed	2 / 239 (0.84%)	7 / 369 (1.90%)	2 / 158 (1.27%)	2 / 486 (0.41%)
occurrences causally related to treatment / all	2 / 2	1 / 7	1 / 2	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
VESTIBULAR NEURONITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
VIRAL INFECTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	1 / 486 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
VIRAL PERICARDITIS
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
VIRAL UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
WOUND INFECTION
subjects affected / exposed	0 / 239 (0.00%)	0 / 369 (0.00%)	1 / 158 (0.63%)	0 / 486 (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
ZIKA VIRUS INFECTION
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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
Metabolism and nutrition disorders
HYPERGLYCAEMIA
subjects affected / exposed	1 / 239 (0.42%)	0 / 369 (0.00%)	0 / 158 (0.00%)	0 / 486 (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
DEHYDRATION
subjects affected / exposed	0 / 239 (0.00%)	2 / 369 (0.54%)	0 / 158 (0.00%)	1 / 486 (0.21%)
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
HYPONATRAEMIA
subjects affected / exposed	0 / 239 (0.00%)	1 / 369 (0.27%)	0 / 158 (0.00%)	0 / 486 (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

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

Non-serious adverse events	DB PLACEBO	OLE OCRELIZUMAB	OLE PLACEBO	DB OCRELIZUMAB
Total subjects affected by non serious adverse events
subjects affected / exposed	175 / 239 (73.22%)	318 / 369 (86.18%)	134 / 158 (84.81%)	400 / 486 (82.30%)
Injury, poisoning and procedural complications
CONTUSION
subjects affected / exposed	19 / 239 (7.95%)	23 / 369 (6.23%)	9 / 158 (5.70%)	14 / 486 (2.88%)
occurrences all number	22	35	13	19
FALL
subjects affected / exposed	0 / 239 (0.00%)	40 / 369 (10.84%)	16 / 158 (10.13%)	0 / 486 (0.00%)
occurrences all number	0	75	28	0
INFUSION RELATED REACTION
subjects affected / exposed	61 / 239 (25.52%)	56 / 369 (15.18%)	40 / 158 (25.32%)	194 / 486 (39.92%)
occurrences all number	154	178	98	496
SKIN LACERATION
subjects affected / exposed	0 / 239 (0.00%)	12 / 369 (3.25%)	8 / 158 (5.06%)	0 / 486 (0.00%)
occurrences all number	0	14	8	0
Vascular disorders
HYPERTENSION
subjects affected / exposed	0 / 239 (0.00%)	28 / 369 (7.59%)	12 / 158 (7.59%)	0 / 486 (0.00%)
occurrences all number	0	33	12	0
Nervous system disorders
TRIGEMINAL NEURALGIA
subjects affected / exposed	0 / 239 (0.00%)	8 / 369 (2.17%)	9 / 158 (5.70%)	0 / 486 (0.00%)
occurrences all number	0	18	14	0
DIZZINESS
subjects affected / exposed	10 / 239 (4.18%)	14 / 369 (3.79%)	10 / 158 (6.33%)	27 / 486 (5.56%)
occurrences all number	12	17	13	33
HEADACHE
subjects affected / exposed	31 / 239 (12.97%)	41 / 369 (11.11%)	15 / 158 (9.49%)	68 / 486 (13.99%)
occurrences all number	48	73	19	98
General disorders and administration site conditions
FATIGUE
subjects affected / exposed	24 / 239 (10.04%)	24 / 369 (6.50%)	12 / 158 (7.59%)	30 / 486 (6.17%)
occurrences all number	32	30	14	33
ASTHENIA
subjects affected / exposed	0 / 239 (0.00%)	21 / 369 (5.69%)	10 / 158 (6.33%)	0 / 486 (0.00%)
occurrences all number	0	26	11	0
OEDEMA PERIPHERAL
subjects affected / exposed	13 / 239 (5.44%)	22 / 369 (5.96%)	11 / 158 (6.96%)	24 / 486 (4.94%)
occurrences all number	16	25	12	27
PYREXIA
subjects affected / exposed	0 / 239 (0.00%)	23 / 369 (6.23%)	14 / 158 (8.86%)	0 / 486 (0.00%)
occurrences all number	0	39	23	0
INFLUENZA LIKE ILLNESS
subjects affected / exposed	0 / 239 (0.00%)	25 / 369 (6.78%)	10 / 158 (6.33%)	0 / 486 (0.00%)
occurrences all number	0	36	13	0
Gastrointestinal disorders
NAUSEA
subjects affected / exposed	15 / 239 (6.28%)	0 / 369 (0.00%)	0 / 158 (0.00%)	18 / 486 (3.70%)
occurrences all number	20	0	0	24
DIARRHOEA
subjects affected / exposed	12 / 239 (5.02%)	42 / 369 (11.38%)	11 / 158 (6.96%)	27 / 486 (5.56%)
occurrences all number	15	54	15	43
CONSTIPATION
subjects affected / exposed	12 / 239 (5.02%)	23 / 369 (6.23%)	8 / 158 (5.06%)	25 / 486 (5.14%)
occurrences all number	14	23	8	28
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	8 / 239 (3.35%)	38 / 369 (10.30%)	12 / 158 (7.59%)	35 / 486 (7.20%)
occurrences all number	8	45	13	44
Skin and subcutaneous tissue disorders
ECZEMA
subjects affected / exposed	0 / 239 (0.00%)	14 / 369 (3.79%)	8 / 158 (5.06%)	0 / 486 (0.00%)
occurrences all number	0	17	8	0
RASH
subjects affected / exposed	0 / 239 (0.00%)	23 / 369 (6.23%)	5 / 158 (3.16%)	0 / 486 (0.00%)
occurrences all number	0	24	6	0
Psychiatric disorders
INSOMNIA
subjects affected / exposed	15 / 239 (6.28%)	12 / 369 (3.25%)	10 / 158 (6.33%)	28 / 486 (5.76%)
occurrences all number	15	13	10	31
DEPRESSION
subjects affected / exposed	31 / 239 (12.97%)	23 / 369 (6.23%)	9 / 158 (5.70%)	34 / 486 (7.00%)
occurrences all number	35	24	9	35
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	30 / 239 (12.55%)	57 / 369 (15.45%)	23 / 158 (14.56%)	56 / 486 (11.52%)
occurrences all number	39	73	36	66
BACK PAIN
subjects affected / exposed	38 / 239 (15.90%)	54 / 369 (14.63%)	23 / 158 (14.56%)	59 / 486 (12.14%)
occurrences all number	54	70	30	71
MUSCLE SPASMS
subjects affected / exposed	0 / 239 (0.00%)	19 / 369 (5.15%)	6 / 158 (3.80%)	0 / 486 (0.00%)
occurrences all number	0	21	6	0
PAIN IN EXTREMITY
subjects affected / exposed	25 / 239 (10.46%)	33 / 369 (8.94%)	18 / 158 (11.39%)	35 / 486 (7.20%)
occurrences all number	31	38	23	38
Infections and infestations
INFLUENZA
subjects affected / exposed	21 / 239 (8.79%)	39 / 369 (10.57%)	16 / 158 (10.13%)	57 / 486 (11.73%)
occurrences all number	25	59	21	76
BRONCHITIS
subjects affected / exposed	15 / 239 (6.28%)	32 / 369 (8.67%)	11 / 158 (6.96%)	30 / 486 (6.17%)
occurrences all number	21	52	15	40
COVID-19
subjects affected / exposed	0 / 239 (0.00%)	76 / 369 (20.60%)	21 / 158 (13.29%)	0 / 486 (0.00%)
occurrences all number	0	87	22	0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	14 / 239 (5.86%)	56 / 369 (15.18%)	14 / 158 (8.86%)	60 / 486 (12.35%)
occurrences all number	21	110	17	87
TOOTH INFECTION
subjects affected / exposed	0 / 239 (0.00%)	20 / 369 (5.42%)	2 / 158 (1.27%)	0 / 486 (0.00%)
occurrences all number	0	38	2	0
SINUSITIS
subjects affected / exposed	0 / 239 (0.00%)	20 / 369 (5.42%)	6 / 158 (3.80%)	0 / 486 (0.00%)
occurrences all number	0	26	10	0
PNEUMONIA
subjects affected / exposed	0 / 239 (0.00%)	25 / 369 (6.78%)	6 / 158 (3.80%)	0 / 486 (0.00%)
occurrences all number	0	34	6	0
NASOPHARYNGITIS
subjects affected / exposed	63 / 239 (26.36%)	100 / 369 (27.10%)	48 / 158 (30.38%)	117 / 486 (24.07%)
occurrences all number	125	190	95	206
URINARY TRACT INFECTION
subjects affected / exposed	57 / 239 (23.85%)	127 / 369 (34.42%)	44 / 158 (27.85%)	103 / 486 (21.19%)
occurrences all number	117	488	120	255

More information

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Were there any global substantial amendments to the protocol? Yes

03 Mar 2011

Clarification of the implementation of 2 separate infusions 14 days apart throughout the study. Revision of inclusion / exclusion criteria. Addition of plasma and urine sample collection for JC Virus.

09 Apr 2012

This version was not issued and was superseded by protocol WA25046 Version D.

15 Jun 2012

Provision of greater clarity in the protocol language around expedited reporting of serious adverse events (SAEs) to the Sponsor to a time interval of no longer than 24 hours. Addition of wording to the safety section. Revision of the dosing preparation and infusion guidance to simplify the procedures.

06 Feb 2015

Inclusion of more detail with respect to the OLE phase. Inclusion of an update to the Statistical Considerations and Analytical Plan section of the protocol in line with the Statistical Analysis Plan (SAP) for the study:

23 Mar 2016

Objectives and dosing regimen of the OLE phase were clarified in this update. New note that for patients that withdraw from treatment with ocrelizumab and enter Safety Follow- Up, alternative treatments for their MS as judged clinically appropriate by the Treating Investigator are allowed.

24 Sep 2017

Updates to the core safety wording; Additional wording changes were made to align with the most recent version of the core safety text; Addition of Adverse Events of Special Interest (AESI)

03 Aug 2018

Addition of optional collection of biosamples for the Research Biosample Repository taken at a single timepoint during the OLE Phase; Extension of the WA25046 OLE treatment phase to 31 December 2020; Updated language pertaining to impairment of vaccination response

17 Dec 2019

The WA25046 open-label extension (OLE) treatment phase has been extended to 31 December 2022

30 Jul 2020

Amended to incorporate the option of a shorter study drug infusion regimen. The goal of this amendment is to reduce patient burden and facilitate patient management at the infusion center during the ongoing open-label extension phase.

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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