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Clinical Trial Results:
A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) Administered Subcutaneously (SC) to Subjects with Systemic Lupus Erythematosus (SLE)

Summary
EudraCT number	2011-003814-18
Trial protocol	DE HU AT CZ SE BE PT ES DK GB BG IT PL
Global end of trial date	01 Oct 2015

Results information
Results version number	v2(current)
This version publication date	30 Jan 2017
First version publication date	20 May 2016
Other versions	v1
Version creation reason	New data added to full data set End of study information added to the initial results.

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

112341

ISRCTN number

-

US NCT number

NCT01484496

WHO universal trial number (UTN)

-

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1-866 4357343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1-866 4357343,

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

12 Feb 2016

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

01 Oct 2015

Was the trial ended prematurely?

No

Main objective of the trial

• To evaluate the efficacy of belimumab administered SC in adult subjects with SLE. • To evaluate the safety and tolerability of belimumab administered SC in adult subjects with SLE.

Protection of trial subjects

Not applicable

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

16 Nov 2011

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 20

Country: Number of subjects enrolled

Brazil: 77

Country: Number of subjects enrolled

Chile: 16

Country: Number of subjects enrolled

Colombia: 41

Country: Number of subjects enrolled

Croatia: 14

Country: Number of subjects enrolled

Japan: 30

Country: Number of subjects enrolled

Malaysia: 5

Country: Number of subjects enrolled

Mexico: 18

Country: Number of subjects enrolled

Philippines: 75

Country: Number of subjects enrolled

Romania: 29

Country: Number of subjects enrolled

Russian Federation: 19

Country: Number of subjects enrolled

Serbia: 23

Country: Number of subjects enrolled

Taiwan: 40

Country: Number of subjects enrolled

Thailand: 22

Country: Number of subjects enrolled

Ukraine: 27

Country: Number of subjects enrolled

United States: 237

Country: Number of subjects enrolled

Poland: 36

Country: Number of subjects enrolled

Portugal: 15

Country: Number of subjects enrolled

Spain: 4

Country: Number of subjects enrolled

Sweden: 2

Country: Number of subjects enrolled

United Kingdom: 6

Country: Number of subjects enrolled

Austria: 7

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

Bulgaria: 18

Country: Number of subjects enrolled

Czech Republic: 13

Country: Number of subjects enrolled

Denmark: 1

Country: Number of subjects enrolled

France: 7

Country: Number of subjects enrolled

Germany: 16

Country: Number of subjects enrolled

Hungary: 9

Country: Number of subjects enrolled

Italy: 6

Worldwide total number of subjects

836

EEA total number of subjects

186

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)

817

From 65 to 84 years

19

85 years and over

0

Subject disposition

Top of page

Recruitment details

Participants (par.) with active systemic lupus erythematosus (SLE) and who were on appropriate stable standard SLE therapy for a period of at least 30 days prior to Day 0 before entering the study were eligible for participation in the study.

Screening details

A total of 1427 par. were screened, out of these 588 par. were screen failures and 839 par. were randomized, of which 836 par. received at least one dose of study treatment. Participants who successfully completed the initial 52-week Double-blind Phase had a choice to enter into a 6-month Open-label Extension Phase of this study.

Period 1 title

Double-Blind Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Are arms mutually exclusive

Yes

Placebo SC

Arm description

Participants received placebo administered subcutaneously (SC) once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo will be supplied as single-use prefilled syringes; Participants will be dosed with placebo on Day 0 and then weekly through 51 weeks of the treatment period.

Belimumab 200 mg SC

Arm description

Participants received belimumab 200 milligrams (mg) administered SC once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period.

Arm type

Experimental

Investigational medicinal product name

Belimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Belimumab 200 mg for SC injection will be supplied as single-use prefilled syringes; Participants will be dosed with study agent on Day 0 and then weekly through 51 weeks of the treatment period.

Number of subjects in period 1	Placebo SC	Belimumab 200 mg SC
Started	280	556
Completed	214	463
Not completed	66	93
Adverse event, serious fatal	2	2
Consent withdrawn by subject	15	12
Lack of Compliance	2	1
Physician decision	5	1
Unable to Visit Site	-	2
Adverse event, non-fatal	23	38
Treatment Failure	3	6
Lost to follow-up	2	6
Positive Pregnancy	1	6
Lack of efficacy	10	15
Protocol deviation	3	4

Period 2 title

Open-Label Phase

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Open-Label - Placebo SC to Belimumab 200 mg SC

Arm description

Participants received placebo administered subcutaneously (SC) once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period. Participants who completed the Double-Blind phase with active SLE were assessed for eligibility to participate in a 6-month extension phase during which they received open label belimumab 200 mg SC weekly.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo will be supplied as single-use prefilled syringes; Participants will be dosed with placebo on Day 0 and then weekly through 51 weeks of the treatment period plus another 6 months of open label belimumab 200 mg SC weekly.

Open-Label - Belimumab 200 SC to Belimumab 200 mg SC

Arm description

Participants received belimumab 200 milligrams (mg) administered SC once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period. Participants who completed the Double-Blind phase with active SLE were assessed for eligibility to participate in a 6-month extension phase during which they received open label belimumab 200 mg SC weekly.

Arm type

Experimental

Investigational medicinal product name

Belimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Belimumab 200 mg for SC injection will be supplied as single-use prefilled syringes; Participants will be dosed with study agent on Day 0 and then weekly through 51 weeks of the treatment period plus another 6 months of open label belimumab 200 mg SC weekly.

Number of subjects in period 2 ^[1]	Open-Label - Placebo SC to Belimumab 200 mg SC	Open-Label - Belimumab 200 SC to Belimumab 200 mg SC
Started	206	456
Completed	191	434
Not completed	15	22
Adverse event, non-fatal	5	13
Other reason	9	6
Lack of efficacy	1	3

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: A total of 1427 par. were screened, out of these 588 par. were screen failures and 839 par. were randomized, of which 836 par. received at least one dose of study treatment. Participants who successfully completed the initial 52-week Double-blind Phase had a choice to enter into a 6-month Open-label Extension Phase of this study.

Baseline characteristics

Top of page

Reporting group title

Placebo SC

Reporting group description

Participants received placebo administered subcutaneously (SC) once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period.

Reporting group title

Belimumab 200 mg SC

Reporting group description

Participants received belimumab 200 milligrams (mg) administered SC once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period.

Reporting group values	Placebo SC	Belimumab 200 mg SC	Total
Number of subjects	280	556	836
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	39.6 ( 12.61 )	38.1 ( 12.1 )	-
Gender categorical
Units: Subjects
Female	268	521	789
Male	12	35	47
Race
Units: Subjects
White/Caucasian/European Heritage	160	326	486
Middle East/North African Heritage	6	10	16
Central Asian Heritage	0	2	2
East Asian Heritage	15	29	44
Japanese Heritage	16	13	29
South Asian Heritage	0	2	2
Southeast Asian Heritage	32	73	105
African American/African Heritage	30	56	86
American Indian or Alaska Native	21	43	64
Native Hawaiian or Other Pacific Islander	0	2	2

End points

Top of page

Reporting group title

Placebo SC

Reporting group description

Participants received placebo administered subcutaneously (SC) once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period.

Reporting group title

Belimumab 200 mg SC

Reporting group description

Participants received belimumab 200 milligrams (mg) administered SC once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period.

Reporting group title

Open-Label - Placebo SC to Belimumab 200 mg SC

Reporting group description

Participants received placebo administered subcutaneously (SC) once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period. Participants who completed the Double-Blind phase with active SLE were assessed for eligibility to participate in a 6-month extension phase during which they received open label belimumab 200 mg SC weekly.

Reporting group title

Open-Label - Belimumab 200 SC to Belimumab 200 mg SC

Reporting group description

Participants received belimumab 200 milligrams (mg) administered SC once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period. Participants who completed the Double-Blind phase with active SLE were assessed for eligibility to participate in a 6-month extension phase during which they received open label belimumab 200 mg SC weekly.

Primary: Percentage of participants achieving a SRI response at Week 52

Top of page

End point title

Percentage of participants achieving a SRI response at Week 52

End point description

Systemic lupus erythematosus responder index (SRI) response is defined as >=4 point reduction from Baseline in safety of estrogen in lupus national assessment (SELENA) systemic lupus erythematosus disease activity index (SLEDAI) score, no worsening (increase of <0.30 points from Baseline) in physician's global assessment (PGA) and no new british isles lupus assessment group of SLE clinics (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with Baseline. Analysis was performed using a logistic regression model for the comparison between belimumab and placebo with covariates treatment group, Baseline SELENA SLEDAI score (<=9 vs. >=10), Baseline complement levels (low C3 and/or C4 vs. no low C3 or C4) and race (black vs. other). Intention-To-Treat (ITT) Population: comprised of all participants who were randomized and treated with at least one dose of study treatment.

End point type

Primary

End point timeframe

Week 52

End point values	Placebo SC	Belimumab 200 mg SC
Number of subjects analysed	279 ^[1]	554 ^[2]
Units: Percentage of participants
number (not applicable)	48.4	61.4

Notes
[1] - ITT population. Three par. did not have a Baseline PGA assessment; therefore, were not included.
[2] - ITT population. Three par. did not have a Baseline PGA assessment; therefore, were not included.

Statistical analysis 1

Comparison groups

Placebo SC v Belimumab 200 mg SC

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0006

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.68

Confidence interval

level

95%

sides

2-sided

lower limit

1.25

upper limit

2.25

Secondary: Time to first severe flare (as measured by the modified SLE Flare Index)

Top of page

End point title

Time to first severe flare (as measured by the modified SLE Flare Index)

End point description

Time to first severe SLE flare is defined as the number of days from treatment start date until the participant met an event (event date – treatment start date +1). Analyses of severe SLE flare was performed on modified SELENA SLEDAI SLE flare index that excludes severe flares that were triggered only by an increase in SELENA SLEDAI score to >12 (since this may only represent a modest increase in disease activity). Only post-Baseline severe flares were considered. Analysis was performed using a Cox proportional hazards model adjusting for Baseline SELENA SLEDAI score (<=9 vs. >=10), Baseline complement levels, (low C3 and/or C4 vs. no low C3 or C4) and race (black vs. other).

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Placebo SC	Belimumab 200 mg SC
Number of subjects analysed	280 ^[3]	556 ^[4]
Units: Percentage of par. with a severe flare
number (not applicable)	18.2	10.6

Notes
[3] - ITT Population
[4] - ITT Population

Statistical analysis 1

Comparison groups

Belimumab 200 mg SC v Placebo SC

Number of subjects included in analysis

836

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.51

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

0.74

Secondary: Percentage of participants whose average prednisone dose had been reduced by >=25% from Baseline to <=7.5 mg/day during weeks 40 through 52 in participants receiving greater than 7.5 mg/day at Baseline

Top of page

End point title

Percentage of participants whose average prednisone dose had been reduced by >=25% from Baseline to <=7.5 mg/day during weeks 40 through 52 in participants receiving greater than 7.5 mg/day at Baseline

End point description

For the analysis of steroid use, all steroid dosages were converted to a prednisone equivalent in milligrams. The average daily prednisone dose was calculated taking into account all steroids taken intravenously, intramuscularly, SC, intradermally and orally for both SLE and non-SLE reasons. A responder was defined as having a prednisone reduction by >=25% from Baseline to <=7.5 mg/day during Weeks 40 through 52. At Baseline, the average daily prednisone dose was the sum of all prednisone doses over 7 consecutive days up to, but not including Day 0, divided by 7. For this analysis, the average prednisone dose was the total prednisone dose during weeks 40 through 52 divided by the number of days during Weeks 40 through 52. Analysis was performed using a logistic regression model with covariates treatment group, Baseline prednisone dose, Baseline SELENA SLEDAI score, (<=9 vs. >=10), Baseline complement levels (low C3 and/or C4 vs. no low C3 or C4) and race (black vs. other).

End point type

Secondary

End point timeframe

Baseline, Weeks 40 through Week 52

End point values	Placebo SC	Belimumab 200 mg SC
Number of subjects analysed	168 ^[5]	335 ^[6]
Units: Percentage of participants
number (not applicable)	11.9	18.2

Notes
[5] - ITT population. Only participants with Baseline prednisone dose >7.5 mg/day were included.
[6] - ITT population. Only participants with Baseline prednisone dose >7.5 mg/day were included.

Statistical analysis 1

Comparison groups

Placebo SC v Belimumab 200 mg SC

Number of subjects included in analysis

503

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0732

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

2.84

Adverse events

Top of page

Timeframe for reporting adverse events

SAEs and non-serious AEs were collected from the start of study agent administration through 51 weeks of the treatment period (or Exit visit for those par. who withdrew during double-blind treatment) plus another 6 months for open-label treatment period.

Adverse event reporting additional description

Serious adverse events (SAEs) and non-serious AEs were collected in participants of ITT population, comprised of participants who were randomized and treated with at least one dose of study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Placebo SC

Reporting group description

Participants received placebo administered SC once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period.

Reporting group title

Belimumab 200 mg SC

Reporting group description

Participants received belimumab 200 mg administered SC once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period.

Reporting group title

Open-Label - Placebo SC to Belimumab 200 mg SC

Reporting group description

Participants received placebo administered subcutaneously (SC) once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period. Participants who completed the Double-Blind phase with active SLE were assessed for eligibility to participate in a 6-month extension phase during which they received open label belimumab 200 mg SC weekly.

Reporting group title

Open-Label - Belimumab 200 SC to Belimumab 200 mg SC

Reporting group description

Participants received belimumab 200 milligrams (mg) administered SC once weekly through 51 weeks of the treatment period. Participants continued with the stable standard therapy they were receiving during the Screening Period. Participants who completed the Double-Blind phase with active SLE were assessed for eligibility to participate in a 6-month extension phase during which they received open label belimumab 200 mg SC weekly.

Serious adverse events	Placebo SC	Belimumab 200 mg SC	Open-Label - Placebo SC to Belimumab 200 mg SC	Open-Label - Belimumab 200 SC to Belimumab 200 mg SC
Total subjects affected by serious adverse events
subjects affected / exposed	44 / 280 (15.71%)	60 / 556 (10.79%)	14 / 206 (6.80%)	25 / 456 (5.48%)
number of deaths (all causes)	2	3	1	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial cancer
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intraductal proliferative breast lesion
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lipoma of breast
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid neoplasm
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 280 (0.36%)	1 / 556 (0.18%)	1 / 206 (0.49%)	2 / 456 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lupus vasculitis
subjects affected / exposed	2 / 280 (0.71%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 280 (0.00%)	2 / 556 (0.36%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	1 / 280 (0.36%)	2 / 556 (0.36%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 280 (0.00%)	3 / 556 (0.54%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystocele
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polycystic ovaries
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleurisy
subjects affected / exposed	1 / 280 (0.36%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Alveolitis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	1 / 206 (0.49%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary arterial hypertension
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lupus pleurisy
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicidal ideation
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Hepatic enzyme increased
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Troponin increased
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Procedural vomiting
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 280 (0.00%)	2 / 556 (0.36%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 280 (0.36%)	2 / 556 (0.36%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	2 / 280 (0.71%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuropsychiatric lupus
subjects affected / exposed	0 / 280 (0.00%)	2 / 556 (0.36%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 280 (0.36%)	1 / 556 (0.18%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial venous sinus thrombosis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lupus encephalitis
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord paralysis
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Central nervous system lupus
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	3 / 280 (1.07%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	1 / 280 (0.36%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypochromic anaemia
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Antiphospholipid syndrome
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Exfoliation syndrome
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eyelid oedema
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 280 (0.36%)	1 / 556 (0.18%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	2 / 280 (0.71%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 280 (0.00%)	2 / 556 (0.36%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids thrombosed
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mouth ulceration
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis chronic
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lip swelling
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Systemic lupus erythematosus rash
subjects affected / exposed	1 / 280 (0.36%)	2 / 556 (0.36%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angioedema
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug eruption
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash pruritic
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	0 / 280 (0.00%)	4 / 556 (0.72%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lupus nephritis
subjects affected / exposed	1 / 280 (0.36%)	2 / 556 (0.36%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephritis
subjects affected / exposed	1 / 280 (0.36%)	2 / 556 (0.36%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	2 / 280 (0.71%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephritic syndrome
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	2 / 456 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
SLE arthritis
subjects affected / exposed	1 / 280 (0.36%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Costochondritis
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polyarthritis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	2 / 280 (0.71%)	3 / 556 (0.54%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 2	2 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 280 (0.36%)	4 / 556 (0.72%)	1 / 206 (0.49%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	1 / 1	2 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	2 / 280 (0.71%)	3 / 556 (0.54%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 280 (0.00%)	3 / 556 (0.54%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	0 / 280 (0.00%)	2 / 556 (0.36%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Amoebic dysentery
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 280 (0.00%)	2 / 556 (0.36%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Corynebacterium sepsis
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
External ear cellulitis
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gasteroenteritis viral
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes virus infection
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	2 / 206 (0.97%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis bacterial
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perirectal abscess
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchitis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tuberculosis of central nervous system
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 280 (0.36%)	0 / 556 (0.00%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal abscess
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	2 / 206 (0.97%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis bacterial
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mycobacterial infection
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paraspinal abscess
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection staphylococcal
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Electrolyte imbalance
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	0 / 280 (0.00%)	1 / 556 (0.18%)	0 / 206 (0.00%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 280 (0.00%)	0 / 556 (0.00%)	1 / 206 (0.49%)	0 / 456 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0

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

Non-serious adverse events	Placebo SC	Belimumab 200 mg SC	Open-Label - Placebo SC to Belimumab 200 mg SC	Open-Label - Belimumab 200 SC to Belimumab 200 mg SC
Total subjects affected by non serious adverse events
subjects affected / exposed	230 / 280 (82.14%)	440 / 556 (79.14%)	101 / 206 (49.03%)	216 / 456 (47.37%)
Vascular disorders
Hypertension
subjects affected / exposed	14 / 280 (5.00%)	25 / 556 (4.50%)	4 / 206 (1.94%)	2 / 456 (0.44%)
occurrences all number	21	26	4	2
Nervous system disorders
Headache
subjects affected / exposed	25 / 280 (8.93%)	57 / 556 (10.25%)	4 / 206 (1.94%)	10 / 456 (2.19%)
occurrences all number	51	83	7	10
Gastrointestinal disorders
Nausea
subjects affected / exposed	22 / 280 (7.86%)	38 / 556 (6.83%)	1 / 206 (0.49%)	5 / 456 (1.10%)
occurrences all number	30	74	1	5
Diarrhoea
subjects affected / exposed	14 / 280 (5.00%)	27 / 556 (4.86%)	3 / 206 (1.46%)	8 / 456 (1.75%)
occurrences all number	17	38	4	8
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	19 / 280 (6.79%)	22 / 556 (3.96%)	1 / 206 (0.49%)	8 / 456 (1.75%)
occurrences all number	20	26	1	9
Psychiatric disorders
Insomnia
subjects affected / exposed	20 / 280 (7.14%)	18 / 556 (3.24%)	0 / 206 (0.00%)	1 / 456 (0.22%)
occurrences all number	21	20	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	15 / 280 (5.36%)	28 / 556 (5.04%)	4 / 206 (1.94%)	5 / 456 (1.10%)
occurrences all number	16	31	4	5
Arthralgia
subjects affected / exposed	11 / 280 (3.93%)	31 / 556 (5.58%)	6 / 206 (2.91%)	11 / 456 (2.41%)
occurrences all number	11	42	6	11
Infections and infestations
Viral upper respiratory tract infection
subjects affected / exposed	24 / 280 (8.57%)	48 / 556 (8.63%)	9 / 206 (4.37%)	17 / 456 (3.73%)
occurrences all number	32	77	9	22
Nasopharyngitis
subjects affected / exposed	22 / 280 (7.86%)	38 / 556 (6.83%)	9 / 206 (4.37%)	7 / 456 (1.54%)
occurrences all number	30	56	9	8
Urinary tract infection bacterial
subjects affected / exposed	18 / 280 (6.43%)	41 / 556 (7.37%)	2 / 206 (0.97%)	14 / 456 (3.07%)
occurrences all number	22	44	2	16
Upper respiratory tract infection bacterial
subjects affected / exposed	14 / 280 (5.00%)	30 / 556 (5.40%)	3 / 206 (1.46%)	9 / 456 (1.97%)
occurrences all number	15	33	3	11

More information

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Were there any global substantial amendments to the protocol? Yes

30 Aug 2011

Amendment 01 applied to all sites. The composition of the DMC was revised to indicate that at least 3 physicians were included without specifying their specialty areas in order to allow flexibility when constituting the DMC for this study; frequency of prothrombin time (PT) and partial thromboplastin time (PTT) assessments were reduced; and assessment of C-reactive protein (CRP) was removed.

04 Oct 2011

Amendment 02 applied to all sites. The amount of time for subjects to be monitored following self-administration of study agent on the first (Day 0) and second (Day 7) injections was increased from 1 to 3 hours in the treatment and 6-month open label extension phase based on reports of serious hypersensitivity reactions occurring outside of the 2 hour window. The efficacy analysis sections were updated to clarify that if the Day 364 (Week 52) visit is missing, data collected at a visit within 28 days of the Day 364 (Week 52) visit would be used for analysis of the primary and major secondary efficacy endpoints.

17 Nov 2011

Amendment 03 applied to all sites. The DMC monitoring schedule after the first meeting was changed from approximately every 4 months to approximately every 6 months to align the schedule with other trials of belimumab in SLE. The protocol was also modified to delete the long-term extension phase after the 6-month open-label extension. Provision of continuing belimumab treatment to subjects who were benefitting and resided in countries where belimumab was not commercially available was achieved in a separate continuation protocol, in which subjects received IV belimumab every 4 weeks until belimumab was commercially available.

21 Feb 2012

Amendment 04 applied to all sites. Inclusion criteria #6 was amended to recommend that women receiving mycophenolate who relied on oral contraceptives for birth control should employ an additional method (e.g., barrier method). This change was made because mycophenolate mofetil (MMF) and other forms of mycophenolate can affect the metabolism of oral contraceptives and may reduce their effectiveness [CellCept package insert, 2015]. Language was added as a safety precaution to clarify the risk of hypersensitivity reactions, to emphasize patient education about the signs and symptoms of hypersensitivity reactions, and to recommend consideration of an extended period of monitoring (greater than the protocol-specified 3 hours after the first 2 injections) if symptoms of acute hypersensitivity were apparent. The protocol was also modified to indicate that from the time a subject consented to participate in the study and prior to treatment, any SAEs deemed to be related to participation in the study were also collected.

06 Aug 2013

This local amendment applied to sites in the US, UK, Spain, Portugal, Sweden and Denmark. Exclusion criteria 1 and 2 were modified so that treatment with B cell targeted therapy 1 year or more ago was permitted. Previous treatment with belimumab was still not allowed. Literature evidence supported that the majority of patients have largely recovered from immunosuppressive effects of B cell depletion within 1 year after treatment with B cell targeted therapy [Rituxan package insert, 2014]. Also, there were supplementary clinical and laboratory exclusion criteria already in place would that identify and exclude patients with residual immune suppression. Countries that participated in this local amendment were selected based on estimates of subjects with exposure of at least 1 year to B cell targeted therapy.

12 Jun 2014

Amendment 05 applied to all sites. The protocol was modified to clarify the timing of the Exit visit and the requirements for the 8-week follow-up visit and the target window of the first dose of IV belimumab following last dose of SC belimumab was added. Progressive multifocal leukoencephalopathy (PML) text was updated based on new information. PK sampling schedule after Day 168 was modified to allow discontinuation of PK sample collection. PK sections were modified to indicate a subset of samples may be used to characterize serum belimumab biochemical attributes and to describe the methodology to be used for this purpose. In subjects who had a positive antibody response at the 8-week follow-up, timing of additional sample collection was made more flexible.

Were there any global interruptions to the trial? No

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

None reported

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