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Clinical Trial Results:
A phase 3, multicenter, open-label, extension study to assess the safety and tolerability of epratuzumab treatment in systemic lupus erythematosus subjects (EMBODY4)

Summary
EudraCT number	2010-020859-30
Trial protocol	BE ES DE CZ GB HU BG LT IT EE
Global end of trial date	16 Feb 2016

Results information
Results version number	v1
This version publication date	15 Dec 2016
First version publication date	15 Dec 2016
Other versions	v2

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

SL0012

ISRCTN number

-

US NCT number

NCT01408576

WHO universal trial number (UTN)

-

Sponsor organisation name

UCB, Inc.

Sponsor organisation address

1950 Lake Park Drive, Smyrna, United States, GA 30080

Public contact

Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com

Scientific contact

Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.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

18 Apr 2016

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

16 Feb 2016

Was the trial ended prematurely?

Yes

Main objective of the trial

To assess the safety and tolerability of long-term epratuzumab treatment in subjects with systemic lupus erythematosus (SLE)

Protection of trial subjects

Patients were pre-medicated prior to infusion of the investigational medicinal product (IMP) to prevent infusion reactions. During the conduct of the study all subjects were closely monitored.

Background therapy

Epratuzumab treatment is in addition to the subjects’ existing standard care of oral corticosteroids and any immunosuppressants or antimalarials continued from Baseline in the subject’s original double-blind study. In SL0012, corticosteroids are not considered to be included in the category identified as “immunosuppressants.” - Subjects who completed SL0006 or SL0008: For SL0006, the Baseline dose is defined as the dose prior to the first infusion of study drug in SL0003 or SL0004. For SL0008, the Baseline dose is defined as the dose at Visit 2 in SL0007. - Subjects who participated in SL0009 or SL0010: The Baseline dose is defined as the dose at Visit 2 in SL0009 or SL0010 for subjects completing the study, or the dose at Visit 1 in SL0012 for subjects who terminated prematurely (at Week 16 or later) due to lack of efficacy in SL0009 or SL0010.

Evidence for comparator

Not applicable

Actual start date of recruitment

20 Jul 2011

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 35

Country: Number of subjects enrolled

Belgium: 10

Country: Number of subjects enrolled

Brazil: 79

Country: Number of subjects enrolled

Bulgaria: 48

Country: Number of subjects enrolled

Canada: 18

Country: Number of subjects enrolled

Czech Republic: 26

Country: Number of subjects enrolled

Estonia: 3

Country: Number of subjects enrolled

France: 20

Country: Number of subjects enrolled

Germany: 49

Country: Number of subjects enrolled

Hong Kong: 1

Country: Number of subjects enrolled

Hungary: 29

Country: Number of subjects enrolled

Israel: 32

Country: Number of subjects enrolled

Italy: 17

Country: Number of subjects enrolled

Lithuania: 26

Country: Number of subjects enrolled

Mexico: 25

Country: Number of subjects enrolled

Poland: 153

Country: Number of subjects enrolled

Romania: 47

Country: Number of subjects enrolled

Russian Federation: 11

Country: Number of subjects enrolled

South Africa: 16

Country: Number of subjects enrolled

Korea, Republic of: 8

Country: Number of subjects enrolled

Spain: 52

Country: Number of subjects enrolled

Taiwan: 25

Country: Number of subjects enrolled

Ukraine: 52

Country: Number of subjects enrolled

United Kingdom: 16

Country: Number of subjects enrolled

United States: 452

Worldwide total number of subjects

1250

EEA total number of subjects

496

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)

1218

From 65 to 84 years

32

85 years and over

0

Subject disposition

Top of page

Recruitment details

The study started to enroll patients in July 2011 and concluded in February 2016.

Screening details

Participant Flow refers to the Enrolled Set.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Enrollment Cohort 1 Epratuzumab 600 mg per week (ES)

Arm description

Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Arm type

Experimental

Investigational medicinal product name

Epratuzumab

Investigational medicinal product code

Emab

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion: 600 mg per week or 1200 mg every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles.

Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (ES)

Arm description

Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

Arm type

Experimental

Investigational medicinal product name

Epratuzumab

Investigational medicinal product code

Emab

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion: 600 mg per week or 1200 mg every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles.

Enrollment Cohort 2 Epratuzumab 600 mg per week (ES)

Arm description

Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Arm type

Experimental

Investigational medicinal product name

Epratuzumab

Investigational medicinal product code

Emab

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion: 600 mg per week or 1200 mg every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles.

Number of subjects in period 1	Enrollment Cohort 1 Epratuzumab 600 mg per week (ES)	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (ES)	Enrollment Cohort 2 Epratuzumab 600 mg per week (ES)
Started	244	498	508
Completed	56	0	0
Not completed	188	498	508
AE, serious fatal	4	4	1
Consent withdrawn by subject	34	60	66
AE, unknown type	-	1	-
AE, non-serious non-fatal	12	19	11
SAE, non-fatal+AE, non-serious non-fatal	-	1	1
Other reason	10	16	18
Lost to follow-up	10	9	17
SAE, non-fatal	11	23	14
Sponsor terminated study	89	333	330
Lack of efficacy	17	30	48
Protocol deviation	1	2	2

Baseline characteristics

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Reporting group title

Enrollment Cohort 1 Epratuzumab 600 mg per week (ES)

Reporting group description

Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Reporting group title

Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (ES)

Reporting group description

Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

Reporting group title

Enrollment Cohort 2 Epratuzumab 600 mg per week (ES)

Reporting group description

Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Reporting group values	Enrollment Cohort 1 Epratuzumab 600 mg per week (ES)	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (ES)	Enrollment Cohort 2 Epratuzumab 600 mg per week (ES)	Total
Number of subjects	244	498	508	1250
Age Categorical
Units: Subjects
<=18 years	0	4	3	7
Between 18 and 65 years	239	485	487	1211
>=65 years	5	9	18	32
Age Continuous
Units: years
arithmetic mean (standard deviation)	41 ( 12 )	41.9 ( 11.5 )	42.5 ( 11.9 )	-
Gender Categorical
Units: Subjects
Male	18	31	30	79
Female	226	467	478	1171

End points

Top of page

Reporting group title

Enrollment Cohort 1 Epratuzumab 600 mg per week (ES)

Reporting group description

Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Reporting group title

Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (ES)

Reporting group description

Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

Reporting group title

Enrollment Cohort 2 Epratuzumab 600 mg per week (ES)

Reporting group description

Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Subject analysis set title

Enrollment Cohort 1 Epratuzumab 600 mg per week

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Subject analysis set title

Enrollment Cohort 2 Epratuzumab 1200 mg Q2W

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects enrolled after approval of Protocol Amendment 2 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

Subject analysis set title

Enrollment Cohort 2 Epratuzumab 600 mg per week

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects enrolled after approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Subject analysis set title

All Epratuzumab 600 mg per week

Subject analysis set type

Safety analysis

Subject analysis set description

600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Subject analysis set title

All subjects

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects receiving 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles and subjects receiving 1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

Subject analysis set title

Enrollment Cohort 1 Epratuzumab 600 mg per week (FASS1)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Subset 1 (FASS1) consisted of all subjects in the FAS who were enrolled in study SL0008, SL0009, or SL0010 prior to enrollment in SL0012. Subjects were enrolled prior to the approval of Protocol Amendment 2. 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Subject analysis set title

Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (FASS1)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Subset 1 (FASS1) consisted of all subjects in the FAS who were enrolled in study SL0008, SL0009, or SL0010 prior to enrollment in SL0012. Subjects were enrolled prior to the approval of Protocol Amendment 2. 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

Subject analysis set title

Enrollment Cohort 2 Epratuzumab 600 mg per week (FASS1)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Subset 1 (FASS1) consisted of all subjects in the FAS who were enrolled in study SL0008, SL0009, or SL0010 prior to enrollment in SL0012. Subjects were enrolled prior to the approval of Protocol Amendment 2. 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Subject analysis set title

All Epratuzumab 600 mg per week (FASS1)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Subset 1 (FASS1) consisted of all subjects in the FAS who were enrolled in study SL0008, SL0009, or SL0010 prior to enrollment in SL0012. Subjects were enrolled prior to the approval of Protocol Amendment 2. 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Subject analysis set title

All subjects (FASS1)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Subset 1 (FASS1) consisted of all subjects in the FAS who were enrolled in study SL0008, SL0009, or SL0010 prior to enrollment in SL0012. Subjects were enrolled prior to the approval of Protocol Amendment 2. Subjects receiving 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles and subjects receiving 1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

Primary: Number of subjects prematurely discontinuing due to a treatment-emergent adverse event (TEAE) during the treatment period (maximum 96 weeks)

Top of page

End point title

Number of subjects prematurely discontinuing due to a treatment-emergent adverse event (TEAE) during the treatment period (maximum 96 weeks) ^[1]

End point description

A TEAE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment.

End point type

Primary

End point timeframe

During the treatment period (through Week 96)

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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.

End point values	Enrollment Cohort 1 Epratuzumab 600 mg per week	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W	Enrollment Cohort 2 Epratuzumab 600 mg per week	All Epratuzumab 600 mg per week	All subjects
Number of subjects analysed	244	497	507	751	1248
Units: Participants
number (not applicable)
Number of Participants	26	45	25	51	96

No statistical analyses for this end point

Primary: Percentage of subjects prematurely discontinuing due to a treatment-emergent adverse event (TEAE) during the treatment period (maximum 96 weeks)

Top of page

End point title

Percentage of subjects prematurely discontinuing due to a treatment-emergent adverse event (TEAE) during the treatment period (maximum 96 weeks) ^[2]

End point description

A TEAE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment.

End point type

Primary

End point timeframe

During the treatment period (through Week 96)

Notes
[2] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.

End point values	Enrollment Cohort 1 Epratuzumab 600 mg per week	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W	Enrollment Cohort 2 Epratuzumab 600 mg per week	All Epratuzumab 600 mg per week	All subjects
Number of subjects analysed	244	497	507	751	1248
Units: percentage of participants
number (not applicable)
Percentage of Participants	10.7	9.1	4.9	6.8	7.7

No statistical analyses for this end point

Primary: Number of subjects reporting at least 1 serious adverse event (SAE) during the treatment period (maximum 96 weeks)

Top of page

End point title

Number of subjects reporting at least 1 serious adverse event (SAE) during the treatment period (maximum 96 weeks) ^[3]

End point description

A SAE is a treatment-emergent adverse event (TEAE) that the investigator classifies as serious. This includes: • Death • Life-threatening • Significant or persistent disability/incapacity • Congenital anomaly/birth defect (including that occurring in a fetus) • Important medical event that, based upon appropriate medical judgment, may jeopardize the patient or subject and may require medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious • Initial inpatient hospitalization or prolongation of hospitalization

End point type

Primary

End point timeframe

During the treatment period (through Week 96)

Notes
[3] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.

End point values	Enrollment Cohort 1 Epratuzumab 600 mg per week	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W	Enrollment Cohort 2 Epratuzumab 600 mg per week	All Epratuzumab 600 mg per week	All subjects
Number of subjects analysed	244	497	507	751	1248
Units: Participants
number (not applicable)
Number of Participants	81	119	104	185	304

No statistical analyses for this end point

Primary: Percentage of subjects reporting at least 1 serious adverse event (SAE) during the treatment period (maximum 96 weeks)

Top of page

End point title

Percentage of subjects reporting at least 1 serious adverse event (SAE) during the treatment period (maximum 96 weeks) ^[4]

End point description

A SAE is a treatment-emergent adverse event (TEAE) that the investigator classifies as serious. This includes: • Death • Life-threatening • Significant or persistent disability/incapacity • Congenital anomaly/birth defect (including that occurring in a fetus) • Important medical event that, based upon appropriate medical judgment, may jeopardize the patient or subject and may require medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious • Initial inpatient hospitalization or prolongation of hospitalization

End point type

Primary

End point timeframe

During the treatment period (through Week 96)

Notes
[4] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.

End point values	Enrollment Cohort 1 Epratuzumab 600 mg per week	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W	Enrollment Cohort 2 Epratuzumab 600 mg per week	All Epratuzumab 600 mg per week	All subjects
Number of subjects analysed	244	497	507	751	1248
Units: percentage of participants
number (not applicable)
Percentage of Participants	33.2	23.9	20.5	24.6	24.4

No statistical analyses for this end point

Secondary: Number of subjects meeting treatment response criteria according to a combined response index

Top of page

End point title

Number of subjects meeting treatment response criteria according to a combined response index

End point description

Combined response index is a response variable (yes/no) incorporating the following criteria for achievement of responder status (ie, all criteria must be met to achieve responder status): (1) British Isles Lupus Activity Group (BILAG) improvement, (2) No worsening in Systemic Lupus Erythematosus Activity Index (SLEDAI), (3) No worsening in Physician’s Global Assessment of Disease, and (4) No disallowed changes in concomitant medications, with disallowed changes including mainly increases in corticosteroids, immunosuppressants, and antimalarials.

End point type

Secondary

End point timeframe

Week 48

End point values	Enrollment Cohort 1 Epratuzumab 600 mg per week (FASS1)	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (FASS1)	Enrollment Cohort 2 Epratuzumab 600 mg per week (FASS1)	All Epratuzumab 600 mg per week (FASS1)	All subjects (FASS1)
Number of subjects analysed	230	488	494	724	1212
Units: Participants
number (not applicable)
Number of Responder	82	146	134	216	362

No statistical analyses for this end point

Secondary: Percentage of subjects meeting treatment response criteria according to a combined response index

Top of page

End point title

Percentage of subjects meeting treatment response criteria according to a combined response index

End point description

Combined response index is a response variable (yes/no) incorporating the following criteria for achievement of responder status (ie, all criteria must be met to achieve responder status): (1) British Isles Lupus Activity Group (BILAG) improvement, (2) No worsening in Systemic Lupus Erythematosus Activity Index (SLEDAI), (3) No worsening in Physician’s Global Assessment of Disease, and (4) No disallowed changes in concomitant medications, with disallowed changes including mainly increases in corticosteroids, immunosuppressants, and antimalarials.

End point type

Secondary

End point timeframe

Week 48

End point values	Enrollment Cohort 1 Epratuzumab 600 mg per week (FASS1)	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (FASS1)	Enrollment Cohort 2 Epratuzumab 600 mg per week (FASS1)	All Epratuzumab 600 mg per week (FASS1)	All subjects (FASS1)
Number of subjects analysed	230	488	494	724	1212
Units: percentage of
number (not applicable)
Percentage of Responder	35.7	29.9	27.1	29.8	29.9

No statistical analyses for this end point

Secondary: Number of subjects meeting treatment response criteria according to a combined response index

Top of page

End point title

Number of subjects meeting treatment response criteria according to a combined response index

End point description

Combined response index is a response variable (yes/no) incorporating the following criteria for achievement of responder status (ie, all criteria must be met to achieve responder status): (1) British Isles Lupus Activity Group (BILAG) improvement, (2) No worsening in Systemic Lupus Erythematosus Activity Index (SLEDAI), (3) No worsening in Physician’s Global Assessment of Disease, and (4) No disallowed changes in concomitant medications, with disallowed changes including mainly increases in corticosteroids, immunosuppressants, and antimalarials.

End point type

Secondary

End point timeframe

Week 96

End point values	Enrollment Cohort 1 Epratuzumab 600 mg per week (FASS1)	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (FASS1)	Enrollment Cohort 2 Epratuzumab 600 mg per week (FASS1)	All Epratuzumab 600 mg per week (FASS1)	All subjects (FASS1)
Number of subjects analysed	230	488	494	724	1212
Units: Participants
number (not applicable)
Number of Responder	74	66	78	152	218

No statistical analyses for this end point

Secondary: The percent of subjects meeting treatment response criteria according to a combined response index

Top of page

End point title

The percent of subjects meeting treatment response criteria according to a combined response index

End point description

Combined response index is a response variable (yes/no) incorporating the following criteria for achievement of responder status (ie, all criteria must be met to achieve responder status): (1) British Isles Lupus Activity Group (BILAG) improvement, (2) No worsening in Systemic Lupus Erythematosus Activity Index (SLEDAI), (3) No worsening in Physician’s Global Assessment of Disease, and (4) No disallowed changes in concomitant medications, with disallowed changes including mainly increases in corticosteroids, immunosuppressants, and antimalarials.

End point type

Secondary

End point timeframe

Week 96

End point values	Enrollment Cohort 1 Epratuzumab 600 mg per week (FASS1)	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (FASS1)	Enrollment Cohort 2 Epratuzumab 600 mg per week (FASS1)	All Epratuzumab 600 mg per week (FASS1)	All subjects (FASS1)
Number of subjects analysed	230	488	494	724	1212
Units: percentage of
number (not applicable)
Percentage of Responder	39.8	21.6	26.2	31.4	27.6

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events were collected from Visit 1 until Safety Follow-Up Visit up to week 196

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Enrollment Cohort 1 Epratuzumab 600 mg per week

Reporting group description

Subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Reporting group title

Enrollment Cohort 2 Epratuzumab 1200 mg Q2W

Reporting group description

Subjects enrolled after approval of Protocol Amendment 2 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

Reporting group title

All Epratuzumab 600 mg per week

Reporting group description

600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Reporting group title

All subjects

Reporting group description

Subjects receiving 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles and subjects receiving 1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

Reporting group title

Enrollment Cohort 2 Epratuzumab 600 mg per week

Reporting group description

Subjects enrolled after approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

Serious adverse events	Enrollment Cohort 1 Epratuzumab 600 mg per week	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W	All Epratuzumab 600 mg per week	All subjects	Enrollment Cohort 2 Epratuzumab 600 mg per week
Total subjects affected by serious adverse events
subjects affected / exposed	81 / 244 (33.20%)	119 / 497 (23.94%)	185 / 751 (24.63%)	304 / 1248 (24.36%)	104 / 507 (20.51%)
number of deaths (all causes)	4	4	5	9	1
number of deaths resulting from adverse events	1	0	1	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	3 / 751 (0.40%)	3 / 1248 (0.24%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	0 / 751 (0.00%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma pancreas
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
Bladder cancer
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer stage I
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervix carcinoma stage 0
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myeloproliferative disorder
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian adenoma
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	3 / 244 (1.23%)	0 / 497 (0.00%)	5 / 751 (0.67%)	5 / 1248 (0.40%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	1 / 3	0 / 0	1 / 5	1 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 244 (0.00%)	3 / 497 (0.60%)	0 / 751 (0.00%)	3 / 1248 (0.24%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	0 / 751 (0.00%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arterial occlusive disease
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Temporal arteritis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Abortion induced
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystectomy
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip arthroplasty
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint arthroplasty
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polymedication
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Shoulder operation
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Cerebral infarction
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abortion spontaneous
subjects affected / exposed	3 / 244 (1.23%)	0 / 497 (0.00%)	4 / 751 (0.53%)	4 / 1248 (0.32%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 4	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foetal death
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Premature delivery
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 244 (0.41%)	4 / 497 (0.80%)	9 / 751 (1.20%)	13 / 1248 (1.04%)	8 / 507 (1.58%)
occurrences causally related to treatment / all	0 / 1	0 / 4	1 / 10	1 / 14	1 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	2 / 244 (0.82%)	2 / 497 (0.40%)	2 / 751 (0.27%)	4 / 1248 (0.32%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 244 (0.41%)	2 / 497 (0.40%)	2 / 751 (0.27%)	4 / 1248 (0.32%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 2	1 / 2	1 / 4	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
Asthenia
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug interaction
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug intolerance
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Local swelling
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Serositis
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	3 / 751 (0.40%)	4 / 1248 (0.32%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	2 / 244 (0.82%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical dysplasia
subjects affected / exposed	2 / 244 (0.82%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Menorrhagia
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenomyosis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic pain
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal prolapse
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 244 (0.41%)	3 / 497 (0.60%)	2 / 751 (0.27%)	5 / 1248 (0.40%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 244 (0.82%)	0 / 497 (0.00%)	3 / 751 (0.40%)	3 / 1248 (0.24%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	0 / 751 (0.00%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute pulmonary oedema
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic respiratory failure
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Emphysema
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal stenosis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary arterial hypertension
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Wheezing
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	2 / 751 (0.27%)	4 / 1248 (0.32%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	2 / 751 (0.27%)	4 / 1248 (0.32%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	0 / 751 (0.00%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	2 / 244 (0.82%)	2 / 497 (0.40%)	2 / 751 (0.27%)	4 / 1248 (0.32%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	3 / 751 (0.40%)	3 / 1248 (0.24%)	3 / 507 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis migration
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic steatosis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Biopsy liver
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood cortisol decreased
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Meniscus injury
subjects affected / exposed	3 / 244 (1.23%)	0 / 497 (0.00%)	3 / 751 (0.40%)	3 / 1248 (0.24%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	2 / 244 (0.82%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Sternal fracture
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Accidental overdose
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
Concussion
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Delayed recovery from anaesthesia
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nail avulsion
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal column injury
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon injury
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Factor VII deficiency
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	2 / 244 (0.82%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleuropericarditis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinoatrial block
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	4 / 751 (0.53%)	6 / 1248 (0.48%)	4 / 507 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 2	1 / 5	1 / 7	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	3 / 244 (1.23%)	0 / 497 (0.00%)	6 / 751 (0.80%)	6 / 1248 (0.48%)	3 / 507 (0.59%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 6	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	4 / 751 (0.53%)	4 / 1248 (0.32%)	3 / 507 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 4	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
Migraine
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	2 / 751 (0.27%)	4 / 1248 (0.32%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 244 (0.00%)	3 / 497 (0.60%)	1 / 751 (0.13%)	4 / 1248 (0.32%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 1	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	1 / 751 (0.13%)	3 / 1248 (0.24%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	1 / 751 (0.13%)	3 / 1248 (0.24%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	0 / 244 (0.00%)	3 / 497 (0.60%)	0 / 751 (0.00%)	3 / 1248 (0.24%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	0 / 751 (0.00%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Grand mal convulsion
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Monoparesis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Altered state of consciousness
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrospinal fluid leakage
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular disorder
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lupus encephalitis
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Memory impairment
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Motor dysfunction
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myasthenia gravis
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuropsychiatric lupus
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Optic neuritis
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radiculitis brachial
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure anoxic
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus headache
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thecal sac compression
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thoracic outlet syndrome
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transverse sinus thrombosis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VIIth nerve paralysis
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 244 (0.41%)	2 / 497 (0.40%)	2 / 751 (0.27%)	4 / 1248 (0.32%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 3	1 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 2	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	1 / 751 (0.13%)	3 / 1248 (0.24%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 1	2 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eosinophilia
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic diathesis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenic cyst
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Amaurosis fugax
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Necrotising retinitis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Panophthalmitis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal disorder
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	1 / 244 (0.41%)	3 / 497 (0.60%)	4 / 751 (0.53%)	7 / 1248 (0.56%)	3 / 507 (0.59%)
occurrences causally related to treatment / all	0 / 2	1 / 3	1 / 5	2 / 8	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 244 (0.00%)	3 / 497 (0.60%)	3 / 751 (0.40%)	6 / 1248 (0.48%)	3 / 507 (0.59%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 3	1 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 244 (0.41%)	3 / 497 (0.60%)	2 / 751 (0.27%)	5 / 1248 (0.40%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	1 / 1	1 / 3	1 / 2	2 / 5	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
Nausea
subjects affected / exposed	2 / 244 (0.82%)	1 / 497 (0.20%)	3 / 751 (0.40%)	4 / 1248 (0.32%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	1 / 3	1 / 1	1 / 4	2 / 5	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
Pancreatitis
subjects affected / exposed	0 / 244 (0.00%)	3 / 497 (0.60%)	1 / 751 (0.13%)	4 / 1248 (0.32%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 1	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eosinophilic colitis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis haemorrhagic
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inflammatory bowel disease
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedematous pancreatitis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal disorder
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal motility disorder
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal spasm
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peptic ulcer
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal haemorrhage
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salivary gland calculus
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin ulcer
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cutaneous vasculitis
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blister
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic cutaneous lupus erythematosus
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pruritus generalised
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic lupus erythematosus rash
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Lupus nephritis
subjects affected / exposed	2 / 244 (0.82%)	3 / 497 (0.60%)	3 / 751 (0.40%)	6 / 1248 (0.48%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 2	1 / 3	1 / 3	2 / 6	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	2 / 751 (0.27%)	4 / 1248 (0.32%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	2 / 244 (0.82%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glomerulonephritis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glomerulonephritis membranoproliferative
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Kidney fibrosis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephritis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stress urinary incontinence
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Toxic nodular goitre
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Troponin increased
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic lupus erythematosus
subjects affected / exposed	7 / 244 (2.87%)	13 / 497 (2.62%)	19 / 751 (2.53%)	32 / 1248 (2.56%)	12 / 507 (2.37%)
occurrences causally related to treatment / all	0 / 7	2 / 15	1 / 19	3 / 34	1 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 244 (0.41%)	2 / 497 (0.40%)	3 / 751 (0.40%)	5 / 1248 (0.40%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 3	0 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	1 / 244 (0.41%)	2 / 497 (0.40%)	2 / 751 (0.27%)	4 / 1248 (0.32%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	3 / 751 (0.40%)	4 / 1248 (0.32%)	3 / 507 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	2 / 244 (0.82%)	0 / 497 (0.00%)	3 / 751 (0.40%)	3 / 1248 (0.24%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc disorder
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	0 / 751 (0.00%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chondromalacia
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enthesopathy
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fasciitis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoporotic fracture
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Patellofemoral pain syndrome
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Periarthritis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SLE arthritis
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue necrosis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Synovial cyst
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tenosynovitis stenosans
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuroendocrine carcinoma of the skin
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	6 / 244 (2.46%)	7 / 497 (1.41%)	15 / 751 (2.00%)	22 / 1248 (1.76%)	9 / 507 (1.78%)
occurrences causally related to treatment / all	1 / 6	0 / 7	7 / 16	7 / 23	6 / 10
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Sepsis
subjects affected / exposed	3 / 244 (1.23%)	3 / 497 (0.60%)	7 / 751 (0.93%)	10 / 1248 (0.80%)	4 / 507 (0.79%)
occurrences causally related to treatment / all	2 / 4	0 / 3	4 / 8	4 / 11	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Cellulitis
subjects affected / exposed	1 / 244 (0.41%)	4 / 497 (0.80%)	4 / 751 (0.53%)	8 / 1248 (0.64%)	3 / 507 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 6	0 / 10	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 244 (0.82%)	3 / 497 (0.60%)	4 / 751 (0.53%)	7 / 1248 (0.56%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 2	1 / 3	0 / 4	1 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	1 / 244 (0.41%)	2 / 497 (0.40%)	1 / 751 (0.13%)	3 / 1248 (0.24%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 3	1 / 1	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 2	2 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 244 (0.82%)	0 / 497 (0.00%)	3 / 751 (0.40%)	3 / 1248 (0.24%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 3	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	3 / 751 (0.40%)	3 / 1248 (0.24%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	0 / 751 (0.00%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis viral
subjects affected / exposed	1 / 244 (0.41%)	1 / 497 (0.20%)	1 / 751 (0.13%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 244 (0.00%)	2 / 497 (0.40%)	0 / 751 (0.00%)	2 / 1248 (0.16%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	2 / 751 (0.27%)	2 / 1248 (0.16%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus chorioretinitis
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epstein-Barr virus infection
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma infection
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic inflammatory disease
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Perineal abscess
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia legionella
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia streptococcal
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salpingitis
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	2 / 751 (0.27%)	3 / 1248 (0.24%)	2 / 507 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 244 (0.41%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 244 (0.00%)	0 / 497 (0.00%)	1 / 751 (0.13%)	1 / 1248 (0.08%)	1 / 507 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 244 (0.00%)	1 / 497 (0.20%)	0 / 751 (0.00%)	1 / 1248 (0.08%)	0 / 507 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Enrollment Cohort 1 Epratuzumab 600 mg per week	Enrollment Cohort 2 Epratuzumab 1200 mg Q2W	All Epratuzumab 600 mg per week	All subjects	Enrollment Cohort 2 Epratuzumab 600 mg per week
Total subjects affected by non serious adverse events
subjects affected / exposed	177 / 244 (72.54%)	296 / 497 (59.56%)	483 / 751 (64.31%)	779 / 1248 (62.42%)	306 / 507 (60.36%)
Vascular disorders
Hypertension
subjects affected / exposed	17 / 244 (6.97%)	26 / 497 (5.23%)	43 / 751 (5.73%)	69 / 1248 (5.53%)	26 / 507 (5.13%)
occurrences all number	19	28	46	74	27
Nervous system disorders
Headache
subjects affected / exposed	46 / 244 (18.85%)	67 / 497 (13.48%)	103 / 751 (13.72%)	170 / 1248 (13.62%)	57 / 507 (11.24%)
occurrences all number	66	84	146	230	80
Dizziness
subjects affected / exposed	20 / 244 (8.20%)	23 / 497 (4.63%)	43 / 751 (5.73%)	66 / 1248 (5.29%)	23 / 507 (4.54%)
occurrences all number	26	30	51	81	25
Hypoaesthesia
subjects affected / exposed	13 / 244 (5.33%)	9 / 497 (1.81%)	25 / 751 (3.33%)	34 / 1248 (2.72%)	12 / 507 (2.37%)
occurrences all number	15	9	28	37	13
Gastrointestinal disorders
Nausea
subjects affected / exposed	39 / 244 (15.98%)	59 / 497 (11.87%)	101 / 751 (13.45%)	160 / 1248 (12.82%)	62 / 507 (12.23%)
occurrences all number	80	86	159	245	79
Diarrhoea
subjects affected / exposed	27 / 244 (11.07%)	47 / 497 (9.46%)	47 / 751 (6.26%)	108 / 1248 (8.65%)	34 / 507 (6.71%)
occurrences all number	41	58	61	146	47
Vomiting
subjects affected / exposed	22 / 244 (9.02%)	32 / 497 (6.44%)	51 / 751 (6.79%)	83 / 1248 (6.65%)	29 / 507 (5.72%)
occurrences all number	45	43	83	126	38
Fatigue
subjects affected / exposed	17 / 244 (6.97%)	19 / 497 (3.82%)	38 / 751 (5.06%)	57 / 1248 (4.57%)	21 / 507 (4.14%)
occurrences all number	24	22	46	68	22
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	21 / 244 (8.61%)	30 / 497 (6.04%)	53 / 751 (7.06%)	83 / 1248 (6.65%)	32 / 507 (6.31%)
occurrences all number	25	31	68	99	43
Oropharyngeal pain
subjects affected / exposed	15 / 244 (6.15%)	9 / 497 (1.81%)	29 / 751 (3.86%)	38 / 1248 (3.04%)	14 / 507 (2.76%)
occurrences all number	24	11	40	51	16
Urticaria
subjects affected / exposed	13 / 244 (5.33%)	7 / 497 (1.41%)	17 / 751 (2.26%)	24 / 1248 (1.92%)	4 / 507 (0.79%)
occurrences all number	20	7	24	31	4
Psychiatric disorders
Depression
subjects affected / exposed	16 / 244 (6.56%)	23 / 497 (4.63%)	31 / 751 (4.13%)	54 / 1248 (4.33%)	15 / 507 (2.96%)
occurrences all number	17	23	33	56	16
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	34 / 244 (13.93%)	31 / 497 (6.24%)	66 / 751 (8.79%)	97 / 1248 (7.77%)	32 / 507 (6.31%)
occurrences all number	47	32	79	111	32
Arthralgia
subjects affected / exposed	24 / 244 (9.84%)	36 / 497 (7.24%)	54 / 751 (7.19%)	90 / 1248 (7.21%)	30 / 507 (5.92%)
occurrences all number	40	44	78	122	38
Systemic lupus erythematosus
subjects affected / exposed	15 / 244 (6.15%)	18 / 497 (3.62%)	38 / 751 (5.06%)	56 / 1248 (4.49%)	23 / 507 (4.54%)
occurrences all number	19	26	49	75	30
Pain in extremity
subjects affected / exposed	15 / 244 (6.15%)	15 / 497 (3.02%)	34 / 751 (4.53%)	49 / 1248 (3.93%)	19 / 507 (3.75%)
occurrences all number	21	17	42	59	21
Muscle spasms
subjects affected / exposed	13 / 244 (5.33%)	18 / 497 (3.62%)	19 / 751 (2.53%)	37 / 1248 (2.96%)	6 / 507 (1.18%)
occurrences all number	14	20	21	41	7
Bursitis
subjects affected / exposed	15 / 244 (6.15%)	9 / 497 (1.81%)	22 / 751 (2.93%)	31 / 1248 (2.48%)	7 / 507 (1.38%)
occurrences all number	24	11	31	42	7
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	66 / 244 (27.05%)	76 / 497 (15.29%)	148 / 751 (19.71%)	224 / 1248 (17.95%)	82 / 507 (16.17%)
occurrences all number	140	126	260	386	120
Urinary tract infection
subjects affected / exposed	56 / 244 (22.95%)	61 / 497 (12.27%)	118 / 751 (15.71%)	179 / 1248 (14.34%)	62 / 507 (12.23%)
occurrences all number	124	88	214	302	90
Nasopharyngitis
subjects affected / exposed	38 / 244 (15.57%)	42 / 497 (8.45%)	83 / 751 (11.05%)	125 / 1248 (10.02%)	45 / 507 (8.88%)
occurrences all number	56	65	123	188	67
Bronchitis
subjects affected / exposed	34 / 244 (13.93%)	35 / 497 (7.04%)	69 / 751 (9.19%)	104 / 1248 (8.33%)	35 / 507 (6.90%)
occurrences all number	38	38	79	117	41
Sinusitis
subjects affected / exposed	25 / 244 (10.25%)	41 / 497 (8.25%)	63 / 751 (8.39%)	104 / 1248 (8.33%)	38 / 507 (7.50%)
occurrences all number	40	48	88	136	48
Influenza
subjects affected / exposed	15 / 244 (6.15%)	22 / 497 (4.43%)	36 / 751 (4.79%)	58 / 1248 (4.65%)	21 / 507 (4.14%)
occurrences all number	16	24	39	63	23
Gastroenteritis
subjects affected / exposed	14 / 244 (5.74%)	19 / 497 (3.82%)	31 / 751 (4.13%)	50 / 1248 (4.01%)	17 / 507 (3.35%)
occurrences all number	14	21	37	58	23
Conjunctivitis
subjects affected / exposed	14 / 244 (5.74%)	15 / 497 (3.02%)	22 / 751 (2.93%)	37 / 1248 (2.96%)	8 / 507 (1.58%)
occurrences all number	16	17	24	41	8

More information

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Were there any global substantial amendments to the protocol? Yes

04 Apr 2011

The protocol was amended to allow subjects completing the Phase 2, Open-Label-Extension (OLE) studies, SL0006 and SL0008, to enroll in SL0012. In addition, a few clarifications, inconsistencies, and typographical errors were made/corrected within the protocol text.

03 Feb 2012

The protocol was amended for the following reasons: - To add an additional treatment arm of epratuzumab 1200mg every other week (QOW) to collect long-term safety data on this dose in a Phase 3 open-label study, in addition to safety data currently being collected in the Phase 3, placebo-controlled, double-blind studies (ie, in SL0009 and SL0010). - To update the statistical considerations (Section 14.2 and Section 14.8 of the protocol) in accordance with addition of the epratuzumab 1200mg QOW treatment arm. - To clarify the guidance for concomitant corticosteroid use in Section 7.8.1.1 of the protocol. The previous text allowed corticosteroid increases for up to 1 month. The revised text specified that corticosteroid increases were allowed for up to 30 consecutive days or up to a total of 30 days per study year. - To update criterion 4 of the primary efficacy variable in Section 4.1.1 of the protocol regarding concomitant corticosteroid use, so that it was consistent with the updated text in Section 7.8.1.1 of the protocol described above. The previous text allowed corticosteroid increases for up to 1 month. The revised text specified that corticosteroid increases were allowed for up to 30 consecutive days or up to a total of 30 days per study year. - To add an additional exploratory endpoint for assessment of flares. - To include a list of anticipated serious adverse events (SAEs) in compliance with the recent Food and Drug Administration (FDA) final rule on safety reporting requirements for studies conducted under an open Investigational New Drug Application (FDA, Guidance for Industry and Investigators, 2011). - To change the name and contact information of the Clinical Trial Biostatistician and Study Physician. In addition, a few clarifications, inconsistencies, and typographical errors were made/corrected within the protocol text.

25 Mar 2013

The protocol was amended for the following reasons: - To extend the study duration for an additional 2 years - To update study contact information - To update SAE reporting information - To update information pertaining to SL0006, SL0008, SL0009, and SL0010 Minor typographical errors were corrected throughout the protocol.